Search

Preclinical data suggested that bryostatin-1 (bryo) could potentiate the cytotoxicity of cisplatin when given prior to this drug. We designed a phase I study to achieve tolerable doses and schedules of bryo and cisplatin in combination and in this sequence.Patients with non-hematologic malignancies received bryo followed by cisplatin in several schedules. Bryo was given as an 1 and a 24 h continuous infusion, while cisplatin was always given over 1 h at 50 and 75 mg/m(2); the combined regimen was repeated on an every 3-week and later on an every 2-week schedule. Bryo doses were escalated until recommended phase II doses were defined for each schedule. Patients were evaluated with computerized tomography every 2 cycles.Fifty-three patients were entered. In an every 2-week schedule, the 1-h infusion of bryo became limited by myalgia that was clearly cumulative. With cisplatin 50 mg/m(2) its recommended phase II dose was 30 microg/m(2). In the 3-week schedule, dose-limiting toxicities were mostly related to cisplatin effects while myalgias were tolerable. Pharmacokinetics unfortunately proved to be unreliable due to bryo's erratic extraction. Consistent inhibition of PKC isoform eta (eta) in peripheral blood mononuclear cells was observed following bryo.Bryo can be safely administered with cisplatin with minimal toxicity; however, only four patients achieved an objective response. Modulation of cisplatin cytotoxicity by bryo awaits further insight into the molecular pathways involved.

Purpose: Preclinical and clinical data support the studyof polar-planar compounds such as N-Methylformamide (NMF) inadvanced squamous cell carcinoma of the uterine cervix (SCC).This phase II trial sought to determine the efficacy andtoxicities of NMF in patients with advanced SCC. Patientsand methods: Eligibility for this trial requiredbidimensionally measurable squamous or adenosquamous cellcancer of the uterine cervix incurable by surgery or radiationtherapy, ECOG performance status of ≤2, no prior NMF and nomore than one prior chemotherapy regimen. Patients receivedNMF at 2000 mg/m2 intravenously over 15–30 minutes days 1,8 and 15. The cycle was repeated every 42 days. A single doseescalation of 25%, 500 mg/m2 was made after the firstcycle if the toxicities did not exceed grade I for hepatictoxicity and grade II for nausea and vomiting. Results:From July 1987 through September 1998, 21 patients withadvanced squamous cell carcinoma of the uterine cervix wereentered on study. Two patients were ineligible because therewas no pretreatment SGOT on one and the other deterioratedprior to drug approval. Therefore, 19 patients were include inthe analysis of response and survival. Four were inevaluable,3 due to inappropriate tumor evaluation and I secondary tograde III vomiting, who went off study. These patients wereincluded in the denominator while computing the results. Therewere 2 deaths, one due to pulmonary hemorrhage fromperforation during central venous insertion and one due todisease. 30% (6/19) patients had toxicities, EasternCooperative Oncology Group (ECOG) grade III or higher and 2 ofthese patients suffered multiple grade III toxicities. Therewere no complete or partial responses. Conclusion: Inthis population, NMF in the dose and schedule employedexhibited no clinical activity.

Background: Preclinical data suggested that sustained inhibition of the anabolic enzyme, ribonucleotide reductase (RR), by hydroxyurea (HU) may be critical for the anticancer effects of the drug. A phase I trial of continuous infusion HU with concomitant hyperfractionated, accelerated radiation therapy (CHU-CHRT) was initiated to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of HU in patients with locally advanced squamous cell carcinoma (SCC) of the head and neck. Methods: Patients were required to have histologically-documented and radiographically-staged locally advanced SCC of the hypopharynx (AJC stages II, III or IV), oropharynx (AJC stage IV), or oral cavity (AJC stage IV) not amenable to reasonable surgical resection. Eligible patients had adequate bone marrow, hepatic, and renal function and had to give informed consent. Concomitant, hyperfractionated, accelerated radiation therapy (CHRT) consisted of 1.2 Gy BID (6 hour minimum interfraction interval) on weekdays and 1.2 Gy delivered daily on the weekends to a total tumor dose of 74.4 Gy. Continuous infusion hydroxyurea (CHU) was administered at 0.25–0.375 mg/m2/min as a continuous intravenous infusion daily for 5 days with weekends days off for the duration of the radiation therapy. The dose of HU was increased by 0.125 mg/m2/min between dose levels until DLT was reached in 2/6 patients. If the primary had a complete clinical response and biopsies were negative, planned neck dissections were performed. Results: Fifteen patients were enrolled and are evaluable. The initial dose level, 0.25 mg/m2/min was tolerated by 3/3 patients. At 0.375 mg/m2/min, 3/6 patients experienced grade 3–4 infections, with one patient having a non-fatal, subendocardial infarction. At 0.313 mg/m2/min, no patient experienced DLT. Conclusion: The MTD for CHU-CHRT was 0.313 mg/m2/min. The toxicities were primarily mucosal and a phase II study is in progress.

The purpose of this study was to determine the efficacy and toxicity of amonafide in unresectable or recurrent head and neck cancer and to determine if the degree of toxicity with amonafide correlated with the acetylator phenotype of the patient. Thirty patients were registered on the study and received amonafide, 300 mg/m2, over two hours each day for five consecutive days every 21 days. There was one partial response [39] which lasted four months. The dose limiting toxicity was myelosuppression. Acetylator phenotype was determined prior to treatment using HPLC to quantitate caffeine metabolites in urine samples after administration of caffeine. This pharmacokinetic evaluation was performed in 21 patients and revealed that (17/21) 81% of the patients were slow acetylators and 19% of the patients were rapid acetylators. No association was found between acetylator phenotype and toxicity in our patient population. Based on this study, it appears that amonafide given at 300 mg/m2 for 5 consecutive days every 21 days is not active in squamous cell carcinoma of the head and neck, and that acetylator status does not correlate with toxicity.

A pilot study was performed to assess the feasibility of combining 5-fluorouracil, recombinant alpha-2b-interferon, external radiation therapy and intraluminal high dose rate brachytherapy with surgery in patients with locally advanced esophageal carcinoma. 5-fluorouracil, 750 mg m-2, was administered via continuous 5-day infusion beginning day 1 and weekly thereafter; interferon, 10 mu subcutaneously, was administered three times per week beginning day 1 and sargramostin, 5 micrograms kg-1, was administered on days without 5-fluorouracil. External radiation began on day one using 1.5 daily fractions to 55.5 Gy. Intraluminal brachytherapy was delivered concomitantly once each week for 5 fractions of 4 Gy. None of the first eight patients went to surgery. The external radiation was changed to 1.5 Gy BID to 45 Gy followed by BID intraluminal radiation to 15 Gy. Of the last four patients, there was one case of radiation myelitis. It was found that successful surgery was not possible and excessive toxicities, including radiation myelitis, occurred with this aggressive regimen.

Echinomycin is a novel bifunctional intercalating agent derived from Streptomyces echinatus. A phase II clinical trial of echinomycin in patients with advanced, measurable colorectal cancer was initiated to determine the efficacy and toxicities of this agent. Echinomycin, 1.5 mg/m2, was given initially as a 30- to 60-min infusion every 4 weeks. After 4 episodes of anaphylaxis had occurred among the first 14 patients, the schedule was changed to a 24-h infusion, and an additional 16 patients were treated on this schedule. Treatment was given every 3 weeks. A total of 30 patients were eligible and evaluable; there were 3 (10%; 90% confidence interval, 3%-23%) clinical responses lasting 3, 3+, and 12 months, respectively. The most serious toxicity encountered was anaphylaxis, which occurred in 5 patients, although with no serious sequelae. A premedication regimen with dexamethasone, diphenhydramine, and cimetidine and a change of the duration of the infusion to 24 h reduced the incidence of this complication. Grade 2-3 vomiting occurred among earlier patients treated; however, with the 24-h schedule this toxicity was substantially reduced. The sole important case of hematologic toxicity was a single patient with grade 3 thrombocytopenia. Echinomycin employed in this dose and schedule had modest activity against colorectal cancer, comparable with that observed with 5-fluorouracil. Further studies in patients with gastrointestinal malignancies using a 24-h infusion with a dexamethasone premedication regimen similar to that employed prior to administration of taxol may be warranted.

Biochemical modulation of cytotoxic cancer chemotherapeutic agents is one means of enhancing the activity and selectivity of antitumor drugs. Traditionally this approach has utilized detailed information regarding a particular enzymatic reaction or biochemical pathway to develop potential modulating agents. In contrast, the reported clinical therapeutic activity of IFN in combination with cytotoxic agents has prompted a reexamination of the biochemical actions of the cytokine. Interferon elicits a number of cellular actions that might contribute to its pharmacologic activity, including both direct antitumor effects and host-mediated actions. The best understood are those related to the cytotoxicity of the fluoropyrimidine antimetabolites and include enzymatic reactions involved in fluoropyrimidine metabolic activation, catabolism, and interaction with its target enzyme. However, even in this instance, a mechanistic association of a specific pharmacologic action with therapeutic activity remains to be determined. These studies demonstrate that cytokines and other biologic agents may exert specific biochemical modulations that augment (or potentially attenuate) the activity of the cytotoxic chemotherapeutic agents.

The treatment of most solid tumors remains unsatisfactory. For patients with advanced disease, combination chemotherapy may offer transient palliation, but improvement in overall survival is uncommon. In the area of hematologic malignancies, which are generally more sensitive to chemotherapy, the majority of patients still fail with uncontrolled systemic disease. Biological agents are potentially useful in the treatment of advanced disease, and offer certain advantages as compared with chemotherapy. For example, they may have greater antitumor specificity because of their ability to recruit immunologically active effector cells. Furthermore, they generally have a different spectrum of toxicities from chemotherapeutic agents, so they can be used more effectively in combination therapy. The interferons (IFNs), a family of polypeptides originally identified for their antiviral activity, are a family of biologic agents that are of great interest as anticancer drugs. They demonstrate reproducible antiproliferative effects in vitro [1,2]. They are capable of augmenting multiple immune parameters including natural killer cell activity and antibody-dependent cell-mediated immunity [3,4]. In addition, shortly after their introduction into clinical trials, IFNs were found to induce remissions in tumors generally refractory to chemotherapy, such as melanoma and renal cell carcinoma, and to induce durable, complete remissions in an uncommon variant of chronic lymphocytic leukaemia, hairy cell leukaemia [5-7]. Despite these initial promising results, however, single agent IFNs have failed to exhibit significant antitumor activity against the majority of solid tumors. Shortly after their introduction into clinical trials, interest arose in incorporating IFNs with chemotherapy regimens, as early preclinical studies demonstrated therapeutic synergism for combinations of IFNs and cytotoxic agents [8-10]. In some instances these effects were dramatic; however, these studies also revealed that: (a) IFNs were capable of enhancing the effect of cytotoxic drugs independent of immune stimulation, for example, in in vitro systems or against human tumors explanted to immunoincompetent mice; and (b) the sequence of administration was less important than the drugs with which the IFNs were combined. These early studies, while providing only incomplete guidance for the transition to clinical trials, nevertheless formed the foundation for phase I trials of IFNs and the broadly-active chemotherapeutic agents such as doxorubicin, cyclophosphamide and cisplatin, as well as for drugs for which a specific biochemical interaction with IFN was identified, such as DFMO. While there are substantial preclinical data regarding the interaction of IFNs and cytotoxic agents, much of these data present difficulties in interpretation, thus making translation to the clinical setting difficult. Nevertheless, several recent clinical trials of combination therapy have demonstrated therapeutically successful results, suggesting that these different classes of agents can be combined in the clinic. Regimens combining cytotoxic drugs and IFNs are being tested with greater frequency. Most of these regimens are empirical in design, without regard to IFN/cytotoxic drug interactions. In many regimens, IFNs are combined with cytotoxic drugs with a specific rationale: biochemical modulation, combined chemoand immunotherapy; or host protection. Each is valid; however, the complexity of potential interactions requires close consideration. In order to analyse the currently available data on interactions of chemotherapeutic agents with interferons and partially resolve some of these complex issues, a symposium, "The role of alpha interferon in the biomodulation of disease," was

There is a well documented relationship between small cell carcinoma of the lung and the amine precursor uptake and decarboxylation system of endocrine cells (APUD). We attempted to exploit this association by employing the unique radiopharmaceutical,131I-MIBG, which is recognized and taken up by the APUD system to monitor disease activity in patients with small cell carcinoma of the lung. A total of eight patients with biopsy proven, metastatic small cell carcinoma of the lung were studied.131I-MIBG was synthesized in our laboratory by reacting metaiodobenzylamine synthesized in our laboratory by reacting metaiodobenzylamine hydrochloride with cyanamide with subsequent solid phase radioiodination. A dose of 0.5 mCi radiopharmaceutical was injected and images obtained on a large field of view gamma camera with a high energy parallel hole collimator at 2, 24, and either 48 or 72 h. Images were compared with known focal areas of metastatic disease demonstrable on computed tomographic scan, chest roentgenogram or bone scan. We were unable to detect reproducible correlations between the images produced by conventional radiographic techniques and the images produced by our radiopharmaceutical. We conclude that this agent will probably not be useful for localization of metastatic small cell lung carcinoma.