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Background: ONC201 is a small molecule antagonist of DRD2, a G protein-coupled receptor overexpressed in several malignancies, that has prolonged antitumor efficacy and immunomodulatory properties in preclinical models. The first-in-human trial of ONC201 previously established a recommended phase II dose (RP2D) of 625 mg once every three weeks. Here, we report the results of a phase I study that evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of weekly ONC201., Methods: Patients ≥ 18 years old with an advanced solid tumor refractory to standard treatment were enrolled. Dose escalation proceeded with a 3 + 3 design from 375 mg to 625 mg of ONC201. One cycle, also the dose-limiting toxicity (DLT) window, was 21 days. The primary endpoint was to determine the RP2D of weekly ONC201, which was confirmed in an 11-patient dose expansion cohort., Results: Twenty patients were enrolled: three at 375 mg and 17 at 625 mg of ONC201. The RP2D was defined as 625 mg with no DLT, treatment discontinuation, or dose modifications due to drug-related toxicity. PK profiles were consistent with every-three-week dosing and similar between the first and fourth dose. Serum prolactin and caspase-cleaved cytokeratin-18 induction were detected, along with intratumoral integrated stress response activation and infiltration of granzyme B+ Natural Killer cells. Induction of immune cytokines and effectors was higher in patients who received ONC201 once weekly versus once every three weeks. Stable disease of > 6 months was observed in several prostate and endometrial cancer patients., Conclusions: Weekly, oral ONC201 is well-tolerated and results in enhanced immunostimulatory activity that warrants further investigation., Trial Registration: NCT02250781 (Oral ONC201 in Treating Patients With Advanced Solid Tumors), NCT02324621 (Continuation of Oral ONC201 in Treating Patients With Advanced Solid Tumors).

Objectives: Activation of cell survival pathways such as autophagy represents a potential resistance mechanism to chemotherapy in NSCLC. Preclinical studies report that autophagy inhibition suppresses lung tumor development and progression. We report the safety and efficacy for adding autophagy inhibitor, hydroxychloroquine, to chemotherapy in a phase Ib/II single-arm study in patients with metastatic NSCLC., Patients and Methods: We treated patients with untreated metastatic NSCLC with carboplatin, paclitaxel (and bevacizumab if criteria met) and hydroxychloroquine 200 mg BID. Patients continued on hydroxychloroquine (+/- bevacizumab) maintenance after 4-6 cycles of therapy., Results: We enrolled 40 patients, 8 on phase Ib and 32 on phase II. Forty-three percent were female; 50% with squamous histology. Median age was 62 years (range, 43-73). Thirteen patients developed ≥grade 3 treatment-related adverse event. Common adverse events (all grades) were neutropenia (35%), neuropathy (32.5%), and anemia (32.5%). The objective response rate (ORR) was 33% in the 30 patients (phase II) evaluable for response. Additionally, 20% of the patients demonstrated stable disease (clinical benefit rate of 53%). The median PFS was 3.3 months (95% CI 2.1-6.8 months). In 9 patients with KRAS positive tumors, ORR was 44% and median PFS was higher than expected at 6.4 months (95% CI 1.8-15.6)., Conclusions: Addition of hydroxychloroquine is safe and tolerable with a modest improvement in clinical responses compared to prior studies. Autophagy inhibition may overcome chemotherapy resistance in advanced NSCLC and further study in a more molecularly selected population such as KRAS-positive tumors is warranted., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: We evaluated trends in administration of concurrent chemoradiation therapy (CRT) and how variations in start dates of chemotherapy and radiotherapy affected overall survival (OS) in patients with non-small cell lung cancer (NSCLC) undergoing a course of definitive CRT., Materials and Methods: Cases of NSCLC treated with definitive CRT were obtained from the National Cancer Database. A survival analysis was performed with Kaplan-Meier curves and Cox proportional hazards models. Propensity score matching was conducted., Results: On a national level, only 48.6% of patients began concurrent CRT on the same day. In a propensity-matched population, starting CRT within 6 days was associated with improved OS (17.9 months) compared with starting 7 to 13 days apart (16.5 months; P = .04). Starting dual therapy within 6 days of each other was associated with a 7% reduction in the risk of death (hazard ratio, 0.93; P = .05). Furthermore, in a propensity-matched cohort, starting CRT within 3 days was associated with longer survival (18.7 months) compared with 4 to 6 days apart (17.5 months; P = .02). Starting treatment 4 to 6 days apart was associated with an 8% increased risk of death (hazard ratio, 1.08; P = .04)., Conclusion: A large proportion (48.6%) of patients with unresectable NSCLC do not initiate CRT on the same day as is considered standard by national guidelines. In this population, nonsimultaneous initiation of CRT was associated with differences in OS. Further efforts to understand the mitigating factors and barriers that interfere with timely delivery of concurrent CRT are needed., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: ONC201 is a small-molecule selective antagonist of the G protein-coupled receptor DRD2 that is the founding member of the imipridone class of compounds. A first-in-human phase I study of ONC201 was conducted to determine its recommended phase II dose (RP2D). Experimental Design: This open-label study treated 10 patients during dose escalation with histologically confirmed advanced solid tumors. Patients received ONC201 orally once every 3 weeks, defined as one cycle, at doses from 125 to 625 mg using an accelerated titration design. An additional 18 patients were treated at the RP2D in an expansion phase to collect additional safety, pharmacokinetic, and pharmacodynamic information. Results: No grade >1 drug-related adverse events occurred, and the RP2D was defined as 625 mg. Pharmacokinetic analysis revealed a C max of 1.5 to 7.5 μg/mL (∼3.9-19.4 μmol/L), mean half-life of 11.3 hours, and mean AUC of 37.7 h·μg/L. Pharmacodynamic assays demonstrated induction of caspase-cleaved keratin 18 and prolactin as serum biomarkers of apoptosis and DRD2 antagonism, respectively. No objective responses by RECIST were achieved; however, radiographic regression of several individual metastatic lesions was observed along with prolonged stable disease (>9 cycles) in prostate and endometrial cancer patients. Conclusions: ONC201 is a selective DRD2 antagonist that is well tolerated, achieves micromolar plasma concentrations, and is biologically active in advanced cancer patients when orally administered at 625 mg every 3 weeks. Clin Cancer Res; 23(15); 4163-9. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Purpose: This randomized phase II study was initially designed to test the activity of two dose schedules of lapatinib (GW572016H), an oral, reversible, dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and human EGFR-2 (HER2/neu; HER2), in chemotherapy-naive patients with non-small cell lung cancer (NSCLC); it was later amended to target patients with bronchioloalveolar carcinoma or no smoking history., Experimental Design: Patients with good performance status and recurrent or metastatic NSCLC were randomized to lapatinib (orally, 1,500 mg once daily or 500 mg twice daily) until progression or intolerance. Patients could have had a maximum of one prior systemic therapy (chemotherapy or biological therapy) for NSCLC. Safety and activity were assessed every 4 and 8 weeks, respectively. Tumors were analyzed for EGFR and HER2 mutations and/or amplifications., Results: Of 75 patients in the nontargeted population, 1 (1.3%) had partial response and 16 (21%) had stable disease of >or=24 weeks. No complete or partial responses were observed in 56 patients in the targeted population; 14 (25%) had stable disease of >or=24 weeks. No responses were seen in three patients with EGFR mutations and five with EGFR gene amplification. No mutations in HER2 were found. One of two patients with HER2 amplification had a 51% decrease in tumor size; however, this response was unconfirmed. The most common adverse events were grade 1 or 2 diarrhea, rash, fatigue, nausea, and anorexia. Adverse events were similar across dosing regimens., Conclusions: Lapatinib was well tolerated, with no notable difference in toxicity between treatment groups. Lapatinib monotherapy did not induce a significant number of tumor regressions in NSCLC. Further studies may be warranted to determine whether lapatinib is active in combination with other agents in the treatment of NSCLC.

Purpose: Several new oral chemotherapeutic agents have recently been introduced. Many possess novel mechanisms of action and specific targets that result in different adverse effect profiles from those associated with traditional chemotherapies and hormonal therapies. The potential advantages and challenges associated with oral chemotherapy are discussed., Summary: Use of the oral route is convenient and allows administration to take place at home or in non-traditional settings. However, nausea, difficulty swallowing, patient nonadherence, interactions with drugs and food, other pharmacokinetic factors, and the high cost of treatment can present problems in using these agents by the oral route. Awareness by clinicians of the potential problems with oral chemotherapy can help to avoid or minimize problems that might affect patient outcomes., Conclusion: While bioavailability studies are often an integral part of developing oral agents, their comparisons with parenteral forms are less well documented. However, studies comparing intravenous 5-fluorouracil (5-FU) with oral 5-FU prodrugs have demonstrated that efficacy, safety, and quality of life are not compromised by the use of oral therapy. Finally, these studies, as well as others, reveal patients prefer the oral route of administration.

Phorbol esters activate protein kinase C and modulate a variety of downstream cell signaling pathways. 12-O-tetradecanoylphorbol-13-acetate (TPA) is a phorbol ester that induces differentiation or apoptosis in a variety of cell lines at low concentrations. A phase I dose escalation trial of TPA was undertaken for patients with relapsed or refractory malignancies. The starting dose was 0.063 mg/m2 and most patients were treated with an intravenous infusion of TPA on days 1-5 and 8-12 followed by a 2-week rest period prior to retreatment. Thirty-five patients were treated. A biological assay was used to monitor levels of TPA-like activity in the blood after treatment. Serious adverse events included individual episodes of gross hematuria, a grand mal seizure, syncope, and hypotension. Many patients had transient fatigue, mild dyspnea, fever, rigors, and muscular aches shortly after the infusion. Dose-limiting toxicities included syncope and hypotension at a dose of 0.188 mg/m2. Only a single patient had evidence of tumor response. These studies establish 0.125 mg/m2 as the maximally tolerated dose when TPA is administered on this schedule.

Background: Molecular mechanisms of chemotherapy resistance are present in prostate carcinoma, some of which increase after androgen ablation (AA) therapy. Therefore, the authors hypothesized that chemotherapy in patients with prostate specific antigen (PSA) progression after local therapy, before androgen ablation therapy, will have greater antitumor activity., Methods: Twenty-three hormone-naive patients with PSA progression after prostatectomy or radiation therapy were registered in this study. Twenty-two were treated with 10 mg/m(2) of mitoxantrone initially, followed by 12 mg/m(2) every 3 weeks for a maximum of 8 cycles. Prostatectomy specimens were assessed, when possible, for topoisomerase II alpha, multidrug resistance protein MRP, and bcl-2 by immunohistochemistry., Results: Twenty-two patients received a total of 131 cycles of therapy. Three patients had transient Grade 3 or 4 neutropenia without fever. During treatment, 10 of 22 patients showed a decrease in PSA, without an associated decrease in testosterone. In this group of 10 patients, the mean PSA decrease was 29% at 3 months and 43% at 6 months. Overall, 4 of 22 patients had a decrease in PSA of greater than or equal to 50%. The PSA decreased in three of seven patients whose cancer overexpressed MRP and in three of seven patients who overexpressed bcl-2. No patient with overexpression of topoisomerase II alpha (n = 4) had a decrease in PSA during the study., Conclusions: To the authors' knowledge, this is the first reported study of mitoxantrone in patients with hormone-naive prostate carcinoma and PSA progression after local therapy; mitoxantrone was safe and biochemically active, similar to prior studies in hormone refractory prostate carcinoma, suggesting that critical molecular mechanisms of chemotherapy resistance are present independent of AA. Further studies are warranted to determine whether pharmacogenomic assessment of topoisomerase II, MRP, or bcl-2 may predict for response to mitoxantrone., (Copyright 2001 American Cancer Society.)

Most prostate cancers eventually develop resistance to hormonal therapy and chemotherapies. Many mechanisms for resistance to chemotherapy have been identified. Mutations or inactivation of the p53 suppressor gene and overexpression of bcl-2 are among such mechanisms. Mutations in the p53 gene can lead to resistance to certain chemotherapy agents, and such mutations are seen more often in metastatic than in primary prostate cancers. Thus, agents that are active in the setting of mutated p53 may have some advantage in prostate cancer. Overexpression of bcl-2 occurs frequently in prostate cancer and is associated with both hormonal therapy and chemotherapy resistance. In experimental systems, bcl-2 overexpression occurs after androgen deprivation and transfection of bcl-2 into sensitive cell lines makes them resistant to chemotherapy and hormonal therapies. Bcl-2 can be inactivated by phosphorylation as occurs with taxanes. The retinoids, as a class, can inhibit the growth of resistant cell lines that overexpress bcl-2, and the combination of interferon (IFN) and cis-retinoic acid (CRA) demonstrated increased antitumor activity. In our cell line model the combination of IFN and CRA greatly enhanced the cytotoxicity of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ). Based on these observations, we conducted a phase I/II trial of CRA and IFN-alpha in patients with biochemical recurrence of prostate cancer. Twenty-six percent achieved a decrease of prostate-specific antigen (PSA), which was correlated to elevated serum transforming growth factor-beta. We then conducted a phase I trial of 13-CRA, IFN-alpha, and escalating doses of paclitaxel. Eighteen patients were treated with 1 mg/kg CRA and 1x10(6) unit IFN on days 1 to 4 and paclitaxel at doses from 100 to 175 mg/m2. Eleven patients received the 175 mg/m2 paclitaxel dose. Two patients in the phase I study achieved partial responses (one cervix and one prostate cancer). We subsequently initiated a phase II study of 13-CRA, IFN-alpha, and paclitaxel in hormone refractory prostate cancer. For entry patients must show progressive disease after androgen ablation. To test the mechanism of action, we are assaying peripheral blood monocytes and, when possible, tumor tissue for bcl-2 expression. As our understanding of the mechanisms of tumor resistance to chemotherapy improves, we will be able to design better approaches in treatment targeted to overcome the mechanisms of resistance.

Purpose: To investigate whether dose escalation of megestrol acetate (MA) improves response rate and survival in comparison with standard doses of MA., Patients and Methods: Three hundred sixty-eight patients with metastatic breast cancer, positive and/or unknown estrogen and progesterone receptors, zero or one prior trial of hormonal therapy, and no prior chemotherapy for metastatic disease were prospectively randomized into three groups. The groups of patients received either MA 160 mg/d (one tablet per day), MA 800 mg/d (five tablets per day), or MA 1,600 mg/d (10 tablets per day)., Results: Patient characteristics were well balanced in the three treatment groups. Three hundred sixty-six patients received treatment and were included in the analyses. The response rates were 23%, 27%, and 27% for the 160-mg, 800-mg, and 1,600-mg arms, respectively. Response duration correlated inversely with dose. Median durations of response were 17 months, 14 months, and 8 months for the 160-mg, 800-mg, and 1,600-mg arms, respectively. No significant differences in the treatment arms were noted for time to disease progression or for survival; survival medians were 28 months (low dose), 24 months (mid dose) and 29 months (high dose). The most frequent and troublesome toxicity, weight gain, was dose-related, with approximately 20% of patients on the two higher-dose arms reporting weight gain of more than 20% of their prestudy weight, compared with only 2% in the 160-mg dose arm., Conclusion: With a median follow-up of 8 years, these results demonstrate no advantage for dose escalation of MA in the treatment of metastatic breast cancer.

Background: In a prior Cancer and Leukemia Group B (CALGB) Phase II trial of patients with advanced, previously untreated mesothelioma, dihydro-5-azacytidine (DHAC) demonstrated a 17% response rate, including 1 complete response, with only mild myelosuppression. This Phase II study (CALGB 9031) was conducted to determine the effectiveness of and toxicities that would result from adding cisplatin to DHAC administered to the same patient population., Methods: Thirty-six patients were treated with concurrent DHAC at 1500 mg/m2/day for 5 days by continuous infusion and cisplatin 15 mg/m2 daily for 5 days. Therapy was repeated every 3 weeks. Cisplatin was to be increased to 20 mg/m2 daily in subsequent cycles if toxicity was minimal. Therapy was continued until disease progression or excessive toxicity mandated discontinuation., Results: Overall, 5 objective responses were observed in 29 evaluated patients (objective response rate, 17%). The median duration of response was 6.6 months. Median survival was 6.4 months, with a median time to clinical failure of 2.7 months. The major toxicity noted was significant chest/pericardial pain, as was observed with DHAC alone. There were 2 early deaths of unknown cause on Days 9 and 17 of therapy, respectively. Significant leukopenia was observed in 29% of patients, but there were no neutropenic fevers., Conclusions: The addition of cisplatin to DHAC did not increase the response rate over that observed with DHAC alone in patients with mesothelioma; however, it did increase toxicity, especially leukopenia. This combination is not recommended for further studies involving mesothelioma patients.

Background: An increased risk of second primary cancers has been reported in patients who survive small-cell carcinoma of the lung. The treatment's contribution to the development of second cancers is difficult to assess, in part because the number of long-term survivors seen at any one institution is small. We designed a multi-institution study to investigate the risk among survivors of developing second primary cancers other than small-cell lung carcinoma., Methods: Demographic, smoking, and treatment information were obtained from the medical records of 611 patients who had been cancer free for more than 2 years after therapy for histologically proven small-cell lung cancer, and person-years of follow-up were cumulated. Population-based rates of cancer incidence and mortality were used to estimate the expected number of cancers or deaths. The actuarial risk of second cancers was estimated by the Kaplan-Meier method., Results: Relative to the general population, the risk of all second cancers among these patients (mostly non-small-cell cancers of the lung) was increased 3.5-fold. Second lung cancer risk was increased 13-fold among those who received chest irradiation in comparison to a sevenfold increase among nonirradiated patients. It was higher in those who continued smoking, with evidence of an interaction between chest irradiation and continued smoking (relative risk = 21). Patients treated with various forms of combination chemotherapy had comparable increases in risk (9.4- to 13-fold, overall), except for a 19-fold risk increase among those treated with alkylating agents who continued smoking., Implications: Because of their substantially increased risk, survivors should stop smoking and may consider entering trials of secondary chemoprevention.

The objective of this study was to test the hypothesis that 13-cis-retinoic acid (CRA) and alpha-interferon (IFN-alpha) have antitumor activity in patients with early recurrence of prostate cancer measured by rising prostate-specific antigen (PSA) after local therapy, and that this activity is associated with the increase of plasma transforming growth factor beta1 (TGF-beta1). Thirty patients with a PSA > 7 ng/ml that increased >0.4 ng/ml/month after initial radiation therapy or a PSA > 2.0 ng/ml after prostatectomy were treated with 1 mg/kg/day of CRA and 3 million units of IFN-alpha administered three times per week. Patients were followed clinically with serum measurements of PSA and assessment of toxicity. Biological activity of CRA and IFN-alpha was assessed by the measurement of plasma TGF-beta1. Twenty-six percent of patients had a partial (50% decrease maintained for 1 month) or minimal (<50% decrease maintained for 1 month) biochemical response of PSA, with a median decrease of 23% (11-55%) at 3 months. Plasma TGF-beta1 levels increased with CRA and IFN-alpha therapy and correlated with a decrease in PSA; patients with a decrease in PSA had a 151% increase in TGF-beta1 compared to 27% in patients without a decrease in PSA (P = 0.04). CRA and IFN-alpha can produce transient reduction or stabilization of PSA. The measurement of plasma TGF-beta1 at 1 month of therapy correlates with changes in PSA and may represent a useful marker for the biological effect of these agents; further analysis in larger numbers of patients and methods to optimize these effects should be explored.

Many studies in small cell carcinoma of the lung (SCCL) have demonstrated a high response rate and a potential for cure in a subset of patients. Combination chemotherapy, the cornerstone of all treatment for SCCL, can produce up to 10% long-term, disease-free survival among all patients with SCCL and greater than or equal to 20% survival among patients who present with limited disease. Significant improvements in survival have occurred in all stages of disease, and further investigative efforts are necessary to improve the complete remission rate, the duration of response, and the percentage of long-term, disease-free survivors. The current report, based on the workshop on SCCL held in Ireland under the auspices of the International Association for the Study of Lung Cancer, reviews the current state of the art for chemotherapy and presents potential future directions.

Menogaril, a semisynthetic derivative of nogalomycin, was brought to phase I clinical testing in patients with refractory solid tumors. Twenty-seven patients received 50 evaluable courses. Menogaril was given as a 1-2-hour iv infusion on 5 consecutive days, with courses repeated every 4 weeks, provided there was reversal of all drug-related toxic effects. The starting dose was 3.5 mg/m2/day X 5, with escalations in subsequent cohorts of patients to 56 mg/m2/day X 5. Neutropenia was dose dependent and dose limiting. At 56 mg/m2/day X 5, the median wbc count nadir was 1100/microliter, and two of four patients were hospitalized for fever and suspected bacteremia. At 50 mg/m2/day X 5, the wbc count nadir was 2300/microliter. Platelet toxicity was less severe. Nonhematologic toxicity consisted primarily of local urticaria and moderate to severe phlebitis at the infusion site, which were dose dependent and lasted up to 6 weeks. For phase II studies, the recommended dose of menogaril is 50 mg/m2/day for 5 consecutive days administered as a 2-hour intermittent infusion, repeated every 28 days.

To evaluate the incidence of thrombocytopenia and bleeding among patients with solid tumors treated intensively with chemotherapy, the records of 1274 patients treated between 1972 and 1980 on protocols known to produce significant myelosuppression were reviewed. Three hundred one patients with solid tumors (breast, lung, melanoma, sarcoma, primary brain, testicular, hypernephroma and others) experienced 5063 days of thrombocytopenia (platelet count less than 50,000/microliters) and 670 days of severe thrombocytopenia (platelet count less than 20,000/microliters). The median number of days thrombocytopenia was 6 (range, 1-250). There were only 44 episodes of clinically detectable serious bleeding, primarily gastrointestinal (26/44), during thrombocytopenia and all but seven episodes first occurred at platelet counts between 20,000-50,000/microliters. Fifteen of the 44 bleeding episodes were associated with coagulation abnormalities, 24 occurred during serious infection, and 12 occurred at sites of tumors. One hundred forty-seven of the 301 patients (49%) received platelet transfusions. In 86 thrombocytopenic patients with central nervous system (CNS) tumors, there was no evidence of CNS bleeding during thrombocytopenia. Hemorrhagic deaths were uncommon, and of the 12 patients who died of bleeding, 7 had normal counts. There is a very low incidence of significant thrombocytopenia or bleeding among patients with solid tumors treated with combination chemotherapy or experimental agents escalated to maximally tolerated doses. These data suggest that with respect to thrombocytopenic bleeding intensive treatment of patients with solid tumors can be pursued with relative safety utilizing the standard transfusion supportive measures now widely available.

After stratification for extent of small cell lung cancer, 109 patients were randomized to receive cycles of chemotherapy with cyclophosphamide, doxorubicin, and VP-16-213 [CAVP16 (regimen I)] or to receive CAVP16 to maximum response (minimum of three courses) and then chemotherapy with CCNU, methotrexate, vincristine, and procarbazine (COMP) alternating with CAVP16 (regimen II). A group of patients who achieved complete remission were randomized to receive whole-brain irradiation or to have observation only. Of the 44 patients with limited disease, 28 (64%) achieved a complete remission and 11 (26%) achieved a partial remission. Of the 65 patients with extensive disease, 26 (40%) achieved a complete remission and 28 (46%) achieved a partial remission. There were no significant differences between the regimens in response or survival. The projected median survival times are 14 and 10 months for limited and extensive disease, respectively. Nearly 30% of patients with limited disease will be 2-year, disease-free survivors. Twenty-nine patients were randomized to receive cranial irradiation or observation only; none of the 15 irradiated patients developed cerebral metastases, but five of 14 randomized to observation relapsed in the brain (P = 0.02). One patient died with necropsy evidence of only intracranial disease. The principal hematologic toxic effect was leukopenia. There were 31 febrile episodes (21 infectious) during neutropenia and four toxic deaths. Nonhematologic toxicity was mild. Cranial irradiation in patients who achieve complete remission delays or reduces the incidence of CNS metastases. Although alternating chemotherapy is not beneficial, combination chemotherapy with CAVP16 alone is highly effective treatment modality for small cell.

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.

Thirty-two patients with advanced gynecologic malignancies were treated with m-AMSA, 120 mg/m2 intravenously every 3 weeks. Seventeen patients with advanced carcinoma of the cervix who were treated with m-AMSA had a median performance status (CALGB scale) of 2. There were two partial responses (PR) (14%) in 16 evaluable patients. The median duration of survival was 76 days following the initiation of m-AMSA treatment. In ovarian carcinoma, none of the nine evaluable patients who were treated responded. One PR occurred among four treated patients with endometrial adenocarcinoma. Toxicity was limited to myelosuppression (WBC greater than 2500/micrograms in 29/77 courses, WBC greater than 1500/micrograms in 16/77 courses, platelets greater than 100,000/micrograms in 10/77 courses, and drug-induced anemia in 7/77 courses) and mild to moderate nausea and vomiting (10/31 patients). Three patients required hospitalization for fever and granulocytopenia, and one patient died from drug-induced sepsis. Although toxicity was acceptable in this group of heavily pretreated patients, m-AMSA has limited activity in patients with advanced carcinoma of the cervix and no apparent activity in patients with advanced epithelial ovarian carcinomas. Continued trials are indicated in patients with adenocarcinoma of the endometrium.

Cachexia is often a severe problem in the management of cancer and other illnesses because it adds to the morbidity of the underlying disease and complicates its treatment. Megestrol acetate has been observed anecdotally to produce weight gain. A review of our experience, and our ongoing phase I/II study of high-dose megestrol acetate for breast cancer, revealed that weight gain occurred in nearly one third (27%) of patients at conventional doses (160 mg/d), and that a marked weight gain (median, 5.1 kg; range, 0.9 to 20.1 kg) occurred in 27 of 28 patients with breast cancer during treatment with high doses of megestrol acetate. Subjective improvement in appetite occurred in most patients at low doses and in most patients at high doses. Further, nearly one half (48%) of patients at conventional doses and virtually all patients at high doses experienced an increased sense of well-being. Our data suggest that megestrol acetate has a potential role in producing subjective improvement, sense of well-being, and increase in appetite and weight, and that the effect may be dose related. Further research is necessary to understand the mechanism of appetite stimulation and/or anabolic effect.

Sixty-six newly diagnosed patients with acute nonlymphocytic leukemia received either daunorubicin alone or a combination of daunorubicin, cytosine arabinoside, 6-thioguanine, and pyrimethamine for remission-induction therapy. The two treatment groups were comparable with respect to the two major prognostic factors in this disease, which were age and presence or absence of infection on admission. The two therapies produced similar results with respect to CR rate and median survival results. Single-agent therapy was associated with less frequent utilization of hospital inpatient facilities and fewer platelet transfusions. The four-drug combination did not decrease the incidence of meningeal leukemia. Patients who achieved CR were treated with two half-dose consolidation courses of the successful remission-induction regimen. Subsequently, all patients received cyclophosphamide and guanazole monthly for maintenance therapy. Median durations of remission for both induction-treatment groups were similar (6.8 and 5.6 mos). The therapeutic results with the single agent in this study were not inferior to those obtained with the drug combination tested, as well as most other previously reported combinations of antileukemic drugs.

Twenty-two patients with refractory tumors received 64 courses of iv bolus carboplatin every day X 5, every 4-5 weeks. All patients are evaluable for toxicity and 18 are evaluable for response. For solid tumor phase II studies, a dose of 77 mg/m2/day X 5 is recommended for patients who have received prior chemotherapy. Patients with no prior chemotherapy experience should receive 99 mg/m2/day X 5. The major dose-limiting side effect is dose-related thrombocytopenia. Courses of carboplatin on this schedule should be repeated every 5 weeks to avoid cumulative wbc count toxicity, since leukopenia frequently did not occur until Day 28. Other toxic effects observed were nausea and vomiting and lower-extremity myalgias and arthralgias. There was no evidence of hearing loss, mucosal damage, or changes in liver or renal function tests of any patient while in this study. Therapeutic responses were seen in four patients: one partial response in renal cancer of 9+ months' duration; one partial response in head and neck cancer of 7+ months' duration; and objective responses in melanoma and colorectal carcinoma of 6 months' duration.

N-methylformamide (NMF) is a polar-planar solvent with both cytotoxic and differentiating activity in preclinical models; it also acts as a radiosensitizer. We treated 17 patients with 18 courses of NMF on a schedule of six weekly doses, administered on a rapid intravenous infusion, which were escalated from 875 to 2,000 mg/m2/wk. The predominant toxicity was a dose-related syndrome of fatigue, malaise, nausea, and anorexia, which was reflected by a decrease in performance status (Karnofsky) of greater than or equal to 20% in six of ten patients who received doses greater than or equal to 1,500 mg/m2/wk. Other gastrointestinal toxicities included moderate vomiting and mild diarrhea. Reversible increase of liver enzymes occurred in six of ten patients at doses greater than or equal to 1,500 mg/m2/wk. The maximum tolerated dose on this schedule is 1,500 mg/m2/wk; the dose recommended for phase II studies is 1,125 mg/m2/wk. Future studies of this regimen in a combined modality setting are planned.

One of the prime nutritional concerns in cancer patients is cachexia and deteriorating nutritional status. Cachexia can occur as a result of either treatment or the tumor itself. The progressive malnutrition ultimately affects performance status and organ function. Tolerance to treatment may thus be decreased, which, in turn, may adversely affect toxicity and response. In addition, the deleterious effects of malnutrition on the immune system can increase susceptibility to infection. The weakness and fatigue related to muscle wasting and changes in metabolism affect physical appearance, leading to a loss of self-esteem. Thus, the vicious cycle of cachexia severely impacts on every aspect of daily life. Providing nutritional support and effective treatment may reverse the cachexia. Studies involving caloric supplements alone have not been encouraging. Conversely, studies using megestrol acetate have shown that cancer patients gain weight and that their sense of well-being improves. However, the mechanisms of weight gain remain unknown, and further studies are needed to determine the mechanisms by which appetite is stimulated or catabolism is inhibited or both. Nursing interventions to stimulate appetite and promote greater food intake, coupled with the use of agents that alter metabolism, such as megestrol acetate, may reverse the trend of cachexia and thus provide an increased sense of well-being and improved quality of life.

The intensity of treatment and the extent of restaging necessary to document the level of response to therapy in patients with non-Hodgkin lymphoma (NHL) remains controversial. One hundred patients with advanced non-Hodgkin lymphoma were randomized to treatment with cyclophosphamide, vincristine, plus prednisone or cyclophosphamide, doxorubicin, vincristine, plus prednisone combination chemotherapy. After induction therapy sequential noninvasive restaging including lymphangiogram and 67gallium scan yielded 33 patients in clinical complete remission and 38 patients in partial remission. Twenty of these 38 patients in partial remission had complete normalization of all clinical and chemical tests ("apparent" clinical partial remission); however, lymphangiogram, gallium scan, abdominal sonogram, or abdominal CAT scan remained abnormal. In these 20 patients in "apparent" clinical partial remission, exploratory laparotomy was performed to further assess disease status. Laparotomy revealed evidence of residual disease in only four patients (20%). When correlated with the laparotomies the accuracy of repeat lymphangiograms and gallium scans was 17% and 50% respectively. Thus, restaging lymphangiogram and gallium scan in NHL patients in "apparent" clinical partial remission are inaccurate, and "second look" operations are recommended for accurate appraisal of response to therapy. The assessment of true complete remission should help define the role of aggressive treatment.

In a Phase I study, menogaril (7-OMEN) was administered daily for 5 days/course, every 21-28 days. Dosages of 3.5, 7, 11.5, 17, and 31.5 mg/m2 were infused over 1 h, and dosages of 42, 50, and 56 mg/m2 were infused over 2 h. Pharmacokinetics was studied at all dosages. Plasma and urine samples were collected from 24 patients, and bile samples were also collected from 2 patients. 7-OMEN and metabolites were measured by high performance liquid chromatography. 7-OMEN was the major plasma fluorescent species at all times, with only trace amounts of N-demethyl menogaril observed. 7-OMEN disappeared from plasma biexponentially with t1/2 alpha 0.19 +/- 0.04 (mean +/- SE) h and t1/2 beta 13.22 +/- 1.54 h. Plasma pharmacokinetics of 7-OMEN was linear from 3.5-56 mg/m2; area under the curve increased proportionally with dosage. Total body clearance of 7-OMEN was 28.18 +/- 3.33 liter/m2/h, Vc was 224 +/- 30.8 liter/m2, and Vss was 370 +/- 25.7 liter/m2. Plasma pharmacokinetics of 7-OMEN studied on multiple days of a given course were similar. Urinary excretion of 7-OMEN and fluorescent metabolites accounted for 5.4 +/- 0.4% of the daily dose. Parent compound still represented greater than or equal to 80% of urinary drug fluorescence after 24 h. N-demethyl menogaril was the only other fluorescent drug species detected in urine. In two patients with biliary tract drains, biliary excretion of drug fluorescence accounted for 2.2-4.2% of the daily dose. Only 7-OMEN and N-demethyl menogaril were detected in bile by high performance liquid chromatography and thin layer chromatography. 7-OMEN was the major fluorescent biliary species, but, by 24 h, N-demethyl menogaril accounted for approximately 40% of biliary drug fluorescence. When considered in light of each patient's observed toxicities, excellent relationships were observed between the plasma area under the curve of 7-OMEN and the percentage of decreases in WBC and absolute neutrophil count. These latter findings should be useful in developing more precise and intelligent dosing schemes for 7-OMEN.

Thirty-eight patients with small-cell carcinoma were treated with cyclophosphamide, Adriamycin, and VP16-213 + or - MER. Response and survival of the six patients who received radiotherapy prior to entering the study were inferior compared with patients who received chemotherapy alone. Of 32 previously untreated patients, 13 had limited and 19 had extensive disease. Ninety-seven percent of these 32 responded and 63% achieved complete remission (CR). All patients with limited disease had a response and 77% achieved CR. Patients with extensive and limited disease had 91/2 months (range 1-26 months) and 14 months (range 31/2 -42 + months) median survival, respectively. The median survival for all complete responders irrespective of extent of disease was 16 months (range 6 - 42 + months). Three patients with limited disease are disease free more than 34 + months and off all therapy 10 + to 18 + months. Eighteen of 38 patients required antibiotics for fever during neutropenia. Eight patients had MER fevers and nine had serious infections. There were four drug-related deaths. MER therapy did not influence response rate, drug toxicity, or survival, but did add morbidity. This combination chemotherapy alone is an effective treatment for previously untreated small-cell lung cancer patients regardless of extent of disease.

The optimal dose of progesterone compounds for the treatment of breast cancer is unknown, but there is evidence to suggest a dose-response curve. We are testing the tolerability and efficacy of megestrol acetate administered orally and continuously in doses three to ten times higher than the standard dose of 160 mg/d. We have so far treated 33 patients with metastatic breast cancer and positive or unknown tumor hormone receptor status. Thirty patients had had documented disease progression with previous hormonal therapy, and 22 had failed with previous chemotherapy. Twenty-five patients had objectively measurable metastases. In this heavily pretreated group, the objective response rate was 40%; in addition, 32% of patients had stabilization of disease. Interestingly, ten of 12 patients who had developed disease progression while on standard-dose megestrol acetate therapy had objective response or stabilization on the higher dose. Toxicity was acceptable and reversible and included mild elevations of blood pressure and weight gain. Our results indicate that high-dose megestrol acetate is well-tolerated and highly active in advanced refractory breast cancer, and suggest a dose-response curve for the drug in the treatment of breast cancer.

cis-Diammine(1,1-cyclobutanedicarboxylato)platinum (CBDCA) is a nonnephrotoxic but myelosuppressive analogue of cisplatin (DDP) with greatly reduced protein binding and greatly increased renal excretion. Thus, CBDCA might produce undue toxicity in patients with decreased renal function. Twenty-two patients [14 females and 8 males; median age, 66 (range, 35 to 83); median Karnofsky performance status, 70 (range, 40 to 90)] with refractory tumors and renal dysfunction [creatinine clearance (CCr) 6 to 83 ml/min] were treated with 31 courses of i.v. bolus CBDCA every 4 to 5 weeks. Dosages were determined by pretreatment CCr. Patients with CCr greater than or equal to 40 ml/min received 400 mg/sq m; patients with CCr 20 to 39 ml/min received 250 mg/sq m; and patients with CCr 0 to 19 ml/min received 150 mg/sq m. Toxicities were assessed by weekly clinical and laboratory assessment. Responses were assessed in patients with measurable disease. Plasma pharmacokinetics and urinary excretion of total and ultrafilterable platinum were measured with flameless atomic absorption spectrometry. Observed toxicities were similar to those in patients with normal renal function. Myelosuppression, especially thrombocytopenia, was the major toxicity. Nausea and vomiting were mild to moderate. There was no ototoxicity, neurotoxicity, or nephrotoxicity or reduction in CCr due to CBDCA. Total body clearance of ultrafilterable platinum correlated highly with CCr. The percentage of reduction in platelet count correlated highly and linearly with the area under the curve (AUC) of plasma-ultrafilterable platinum. However, for any AUC, there was 17% greater platelet reduction in patients who had previously received extensive myelosuppressive chemotherapy than in nonpretreated patients. Since total body clearance is proportional to CCr, platelet reduction is proportional to AUC, and total body clearance = dosage/AUC, we have derived an equation to calculate a dosage that will produce a desired reduction in platelet count. Calculations for theoretical patients (both pretreated and nonpretreated) with CCr of 100 ml/min produce dosages very close to maximum tolerated dosages derived in actual Phase I trials. The actual clinical utility of these predictive equations must await validation in prospective studies with larger numbers of patients.

Thirteen patients with relapsed acute leukemia, 12 adults with acute nonlymphocytic leukemia, and one child with acute lymphoblastic leukemia were treated with VP 16-213, an epipodophyllotoxin analog, at a dose of 200-300 mg/m2/day X5 as a 2-hour intravenous infusion. Only four patients achieved bone marrow aplasia and three regenerated with leukemic cells. The fourth patient achieved a partial remission for 4 weeks. Toxicities included myelosuppression (WBC nadir 500/microliter), nausea and vomiting (70% of courses), mucositis (23%), esophagitis (12%), which contributed to death in one patient, hypotension (12%), and transient liver function abnormalities (12%). It is concluded that increasing the dose of VP 16-213 as employed in this study did not increase the therapeutic activity of VP 16-213 for the treatment of relapsed leukemia but did increase the risk of toxicity.

A phase II study of vindesine at a dose of 3 mg/m2 I.V. for 6 weeks and every other week thereafter was carried out in 18 patients with small-cell carcinoma of the lung. All patients were refractory to conventional therapy and all had been treated previously with spindle inhibitors, vincristine, or VP 16-213. All patients were evaluable for response and toxicity. No objective responses were observed. Leukopenia, the only hematologic toxicity, occurred in 13 patients (72%). Neurotoxicity occurred in five patients (28%). Vindesine appears to have limited activity in patients with small-cell carcinoma of the lung previously treated with spindle inhibitors.

Sixteen previously treated patients received AZQ in a phase II study to test therapeutic efficacy in refractory small cell lung cancer. The dose and schedule of AZQ was 20 mg/m2 day 1 and 8, with treatments repeated every 28 days. No objective responses were noted among 16 evaluable patients. Myelosuppression was the major toxicity. AZQ does not appear to have antitumor activity in patients with previously treated small cell carcinoma.

Three patients with metastatic breast carcinoma who had untreated locally advanced primary tumors were treated initially with combination chemotherapy followed by hygienic mastectomy. There was marked regression of the primary tumor in each case after chemotherapy, allowing for a technically simpler mastectomy without skin grafts. There were no serious postoperative complications, or delay in the resumption of systemic chemotherapy in any of them. The postoperative chemotherapy produced complete disappearance of the distant metastases and the patients remain clinically free of disease without local recurrence for 21, 10, and 7 months, respectively. One of these patients had inflammatory carcinoma and did well with this combined approach. These findings suggest a rationale for such an approach in patients with inflammatory carcinoma and may be applicable to patients with stage III breast cancer in whom the primary tumors are locally advanced and technically difficult to resect.