Phase I clinical investigation of 7-con-O-methylnogaril, a new anthracycline antibiotic.

7-con-O-Methylnogaril (menogaril, NSC-269148) is a new anthracycline antibiotic that has been evaluated in a Phase I clinical trial. The drug was administered in a single i.v. infusion over a period of 60 min given every 3 weeks. Twenty-four patients received 64 courses of the drug in a dose range of 16 to 256 mg/m2. Granulocytopenia was dose limiting and prolonged, requiring treatment delay in 5 of 9 patients treated at doses greater than or equal to 192 mg/m2. Concentration dependent phlebitis occurred in 12 patients, and was of minimal severity when the menogaril concentration was less than 1 mg/ml. Hair loss was experienced by 8 patients but was generally mild with only one patient developing total alopecia. Possible acute cardiac toxicity was noted in one patient who had a transient episode of atrial fibrillation following his fifth course of menogaril. Phase II studies of 7-con-O-methylnogaril are planned at a starting dose of 160 mg/m2 for patients with prior chemotherapy or radiotherapy, and 200 mg/m2 for those without prior therapy given at 28-day intervals.

Phase I study of alpha 2-interferon plus doxorubicin in patients with solid tumors.

Cytotoxic chemotherapy and interferon have shown synergistic antitumor activity in vitro. The purpose of this study was to determine the maximally tolerated dose of doxorubicin given every 3 weeks, in patients receiving recombinant alpha 2-interferon [10 X 10(6) IU/m2 s.c. three times per week (Monday, Wednesday, and Friday)] during the first 2 weeks of each cycle of doxorubicin. Fourteen patients received a total of 41 cycles. Hematological toxicity was dose limiting with granulocytopenia (total granulocyte count, less than 1000) occurring in 50% of patients treated with doxorubicin at 40 mg/m2 and in 25% of patients treated with doxorubicin at 30 mg/m2. Nonhematological toxicities included a flu-like syndrome, alopecia, nausea, vomiting, diarrhea, and transient mild increases in liver function tests. A partial response was seen in one patient with metastatic squamous cell carcinoma of the skin and in another patient with metastatic adenocarcinoma of the pancreas. Concomitant administration of recombinant alpha 2-interferon given on this schedule limits the amount of doxorubicin that can be administered. However, the responses noted in this study are encouraging enough to warrant additional studies of doxorubicin plus recombinant alpha 2-interferon.

Phase I clinical trial of carbetimer.

Carbetimer (carbethimer, N-137, NED-137, carboxyimamidate) is a low molecular weight polyelectrolyte with antitumor activity in a variety of tumor models. This phase I trial evaluated a single dose of carbetimer infused over 1-2 h every 28 days. Forty-three patients received 71 courses of the drug at doses ranging from 180 to 8500 mg/m2. The dose-limiting toxicity was hypercalcemia (serum calcium greater than 12.5 mg/dl) noted in two of three patients at a dose of 8500 mg/m2. Serum calcium levels between 10.5 and 12.5 mg/dl were noted in an additional three patients treated at doses greater than or equal to 1600 mg/m2. Calcium balance studies in three patients treated at 6500 mg/m2 revealed an increase in urinary cyclic AMP and phosphate excretion after treatment accompanied by a mild elevation of serum parathyroid hormone. Immunological studies in these patients revealed a statistically significant increase in the percentage of peripheral T-helper cells. An increase in the T-helper/suppressor cell ratio was observed in two of the three patients studied. Interleukin 2 production by phytohemagglutinin-stimulated peripheral mononuclear cells was increased in two of three patients. One patient with a renal cell carcinoma showed a mixed response. The recommended dose for phase II trials as assessed from this study is 6500 mg/m2 as a single dose every 28 days.

Rationale for and conduct of a phase I clinical trial with interferon alfa-2b plus doxorubicin.

A human tumor cloning system was utilized to screen for the antitumor activity of recombinant interferon alfa-2b (Intron A) alone and in combination with standard antineoplastic agents. These in vitro studies confirmed synergistic effects of alfa-2b plus doxorubicin against primary human tumors. Based on those in vitro findings, a phase I study has been conducted by Sarosy and colleagues that demonstrated that recombinant interferon alpha-2b and doxorubicin could be given together. Myelosuppression was the dose-limiting toxicity. Because responses were noted in the phase I trials with the combination, phase II trials of the combination are warranted. Additional phase I studies that should be pursued include recombinant interferon alpha-2b plus 5-fluorouracil, interferon plus cisplatinum, and interferon plus DTIC.

Adjuvant treatment of colorectal cancer. Current status and concepts.

Colorectal cancer is the second leading cause of cancer mortality in the United States, causing approximately 50,000 deaths per year. The overall prognosis and results of treatment have not changed impressively over the last three decades. Half of all the patients who undergo curative surgery finally succumb to locoregional or metastatic recurrence of their disease. Recent clinical research has been aimed at adjuvant therapeutic measures to improve survival after curative surgical resection. For rectal cancer, combined postoperative chemotherapy and radiation therapy have been shown to reduce the overall relapse rate and improve disease-free survival. Further studies of adjuvant treatment for rectal cancer are needed to evaluate the optimal radiation schedule and limit the side-effects of the treatment. Adjuvant treatment of colon cancer must still be regarded as unsettled. Since liver metastases are the most common unfavorable outcome of colon cancer, ongoing trials using liver-directed treatment (perfusion, irradiation) should be followed with interest. The lack of proven efficacy and the side-effects of these treatments strongly favor the inclusion of an observation-only control group in trials for adjuvant treatment of colon cancer. Unfortunately, there is as yet no proven significant benefit from immunotherapy as an adjuvant therapy for colorectal cancer, but further basic and clinical studies will be of great interest in this field.

A phase I and pharmacokinetic comparison of hepatic arterial and peripheral vein infusions of bisantrene for liver cancer.

Bisantrene (NSC-337766) was administered to five patients with cancer of the liver (one case of hepatocellular carcinoma, two of metastatic carcinoma of unknown primary, two of metastatic colorectal carcinoma). Under fluoroscopic guidance, percutaneous hepatic venous catheters were placed in five patients and percutaneous hepatic arterial catheters in four. A fifth patient's hepatic arterial catheter was implanted at laparotomy. Hepatic plasma flow was estimated by the Fick principle using peripheral vein indocyanine green infusion. On the first day of treatment, patients received a 2- or 4 h hepatic arterial infusion of bisantrene (130 mg/m2); peripheral venous, hepatic arterial, and hepatic venous timed blood samples were drawn during and for 18 h after drug infusion. On the second day of treatment, 2- or 4 h peripheral vein infusion of bisantrene (130 mg/m2) was followed by the same blood sampling schedule. Patients were followed weekly for toxicity. Four patients received only one course of treatment, while a fifth received two courses. All patients experienced leukopenia (median nadir 2400/mm3; range 1400-2700/mm3). Two patients developed fever after drug infusion. No antitumor responses were observed. Plasma bisantrene concentrations were measured by HPLC. Pharmacokinetic analyses are reported for four patients. The hepatic extraction ratio ranged from 15% to 49%, hepatic plasma clearances were 0.029-0.353 1/min/m2; peripheral vein areas under the concentration-time curve during hepatic arterial infusion ranged from 35% to 50% of peripheral vein areas under the curve during peripheral vein infusion. We conclude that hepatic arterial bisantrene infusion offers only modest pharmacokinetic advantage to the target organ or to the systemic circulation over peripheral vein infusion.

Malnutrition in lung cancer: incidence, prognostic implications, and pathogenesis.

Malnutrition and weight loss are common in patients with lung cancer. Weight loss is an independent prognostic factor for survival in lung cancer treatment studies. Metabolic disturbances probably play a dominant role in weight loss in these patients rather than reduced food intake. The identification of the pertinent etiologic metabolic abnormalities and development of specific therapeutic intervention should be goals for future research.

Chemotherapy of metastatic gastrointestinal cancers: prospects for future adjuvant systemic therapies.

Overall survival enhancement for patients with gastrointestinal malignancies is most likely to come from the integration of active systemic drug therapies into combined modality programs, applied in the surgical adjuvant or locoregional disease setting. Recent results of chemotherapy trials in advanced disease are discussed with emphasis placed on regimens that appear to be likely candidates for future early-stage disease studies. The ultimate success of this overall strategy depends heavily on identification of new active chemotherapeutic agents. meticulous disease-oriented phase II testing of all new agents in gastrointestinal cancers is critical to this effort.

Hyperthermia and chemotherapy: preclinical considerations.

Malignant cells appear to be selectively sensitive to thermal injury. The precise mechanism of cell death after thermal exposure has not been established, but the phenomenon has been demonstrated by both in vitro and in vivo techniques. Synergy of hyperthermia and chemotherapy has been demonstrated for several agents, but in vitro results are not uniformly confirmed in vivo. In some agents (methyl-CCNU) no synergy was found in vivo. In others (adriamycin) synergy was only demonstrated at drug doses with intolerable toxicity. Studies of the effects of hyperthermia on drug pharmacokinetics are desirable for future clinical trial design.

The rediscovery of DON (6-diazo-5-oxo-L-norleucine).

DON (6-diazo-5-oxo-L-norleucine) and azotomycin are glutamine antagonists that were tested in human malignancies in the 1950s. Azotomycin demonstrated significant activity in colorectal cancer. DON is probably the active form of azotomycin. Recent impressive results for both of these agents in human tumor xenografts (especially the CX-2 colon tumor) have stimulated renewed clinical interest in DON, the more readily available agent. DON mechanism of action, clinical pharmacology, previous clinical data, and current phase I studies are discussed.

Adjuvant chemotherapy in colon and gastric cancer.

The adjuvant chemotherapy of colorectal and gastric cancer is being actively investigated. Studies of both single antineoplastic agents and combinations of several drugs have been used. In colorectal cancer, single-agent therapy has not resulted in improved survival. Combination chemotherapy studies are at too early a stage to be evaluated. In gastric cancer, single-agent chemotherapy has not been effective as adjunctive treatment to surgery. Combinations of active agents in gastric cancer hold promise as effective surgical adjuvant therapy.

Analysis of adjuvant therapy in large bowel cancer.

Since 1958 there has been intense efforts in adjuvant systemic therapy for colorectal cancer. Peri-operative chemotherapy with HN2, TSPA + FUDR produced no clear-cut prolongation of disease-free survival. Short-term (two courses) and long-term (18 months) therapy with 5-FU by the Veterans Administration surgical Adjuvant Group is reported to give marginal increases (7--9%) in survival at 5 years. These findings are confirmed by the COG study of prolonged 5-FU which shows prolongation of disease-free survival of borderline statistical significance for Dukes' C colon (P = 0.051) + rectum (P = 0.016). Short-term benefit to 18 months was conferred by prolonged 5-FU in the VASAG + COG studies, for patients who have had a palliative resection. Combination chemotherapy might be more active, but no results are available from the controlled trials utilizing 5-FU + MeCCNU or immunotherapy. Preoperative irradiation in the VASAG studies resulted in downstaging in terms of operative findings of lymph node involvement and was of survival benefit in those patients have an AP resection for cure or palliation of rectal cancer (P less than 0.02). More intensive preoperative radiation programs are ongoing, as well as postoperative radiation with and without chemotherapy. Further progress awaits the discovery of truly active chemotherapy programs, as well as better techniques of radiation enhancement.

Combined modality treatment of pancreatic cancer: implications for the surgeon.

Since pancreatic cancer is still increasing and has a poor prognosis, there is great interest in improving treatment results by combined modality approaches. This paper considers the most appropriate studies to analyze the status of treatment and future implications for surgeons. With new radiation sources and more sophisticated treatment plans, intra- and post-operative radiotherapy now has an established role in local tumor control. Combination chemotherapy has yielded response rates of 40-45% and improved chemotherapy will play a role in the treatment and perhaps in the prevention of disseminated disease. Although it seems likely that chemotherapy combined with newer radiotherapeutic technique could improve treatment results in advanced pancreatic cancer, treatment-related and limiting toxicity still must be defined. There are suggestions that more surgeons become involved in the combined modality approach, as both radiotherapy and chemotherapy may be more valuable in primary management. The unsatisfactory results of surgical treatment imply the need for adjuvant treatment, which must be tested in randomized multicenter trials. Future efforts will require an interdisciplinary approach to this disease.

Elliptinium, a DNA intercalating agent with broad antitumor activity in a human tumor cloning system.

We have utilized a human tumor cloning system to determine the in vitro antitumor effects of elliptinium, a new DNA intercalating agent. The purpose was to determine which human tumors should be studied in phase II clinical trials with this agent. Eighty-eight out of 282 tumors plated in culture were evaluable for drug-sensitivity assays. The overall in vitro response rate (defined as a less than or equal to 50% survival of tumor colony-forming units compared to control) was 28% at 0.4 micrograms/ml (1/10 of peak plasma level). In vitro activity was noted for elliptinium against breast cancer, renal cell carcinoma, small-cell lung cancer and non small-cell lung cancer. Elliptinium had a higher in vitro activity than adriamycin against this same group of tumors. Six of 25 (24%) adriamycin-resistant tumors were sensitive to elliptimium. Our in vitro response rate in breast cancer correlates with the response rate in phase II clinical trials with this drug. Further phase II clinical trials with elliptinium in patients with renal cell carcinoma, non small-cell lung cancer and small-cell lung cancer are indicated.

Chemotherapeutic alteration of small intestinal morphology and function: a progress report.

Nine patients with malignancy requiring chemotherapy were evaluated before, during, and in the recovery phase of their antineoplastic regimen with selected absorptive studies and jejunal biopsies. Depression of the crypt mitoses occurred without change in the indices of absorption. The mitotic indices returned to pretreatment counts on the recovery phase biopsies. Even after prolonged therapy, restudy in three of the patients failed to demonstrate clinical malabsorption. We conclude that chemotherapy-related malabsorption does not contribute to overall malnutrition of cancer patients during the first months of treatment.

Activity of Carbetimer in a human tumor cloning system.

The antitumor activity of Carbetimer was tested against 171 patient's tumors in a human tumor cloning system. Sixty-seven tumor specimens had adequate growth to be considered evaluable. In 21 specimens survival of tumor colony forming units was less than or equal to 50% that in control plates. Antitumor effect was most impressive in carcinomas of the breast, ovary, and lung. This information will be useful in planning disease oriented Phase II trials.

Tetracycline and quinacrine in the control of malignant pleural effusions. A randomized trial.

Eighteen patients with advanced metastatic malignancy who had 21 pleural effusions requiring sclerosis for control were randomly allocated to intrapleural therapy with tetracycline or quinacrine. Tetracycline produced partial or complete control of the effusion in ten of 12 trials for a median duration of 6 months (range 1.5 to 22 months). Partial or complete control was obtained in nine of ten trials with quinacrine, for a median duration of 3 months (range 1 to 13 months). All complete responders who died achieved control of their effusions until their terminal admissions despite clinical evidence of overt systemic tumor progression in the intervening period. Single-dose tetracycline therapy was accompanied by less fever (p less than 0.04) and less pleuritic pain (p = 0.09) than quinacrine. Tetracycline is effective, well tolerated, easily administered, and should be considered as the initial therapy for malignant pleural effusions requiring pleural sclerosis.

A placebo-controlled trial of ICAM-1 antisense oligonucleotide in the treatment of Crohn's disease.

BACKGROUND & AIMS: Intercellular adhesion molecule 1 (ICAM-1) plays an important role in the trafficking and activation of leukocytes and is up-regulated in inflamed mucosa in Crohn's disease. ISIS 2302 is an antisense phosphorothioate oligodeoxynucleotide that inhibits ICAM-1 expression. The aim of this study was to obtain preliminary assessment of tolerability, pharmacology, and efficacy of ISIS 2302 in Crohn's disease. METHODS: Twenty patients with active, steroid-treated Crohn's disease were randomized (3:1, ISIS 2302 to placebo) to receive over 26 days 13 intravenous infusions of ISIS 2302 (0.5, 1, or 2 mg/kg) or saline placebo in a double-blinded study. The patients were followed up for 6 months. RESULTS: At the end of treatment. 47% (7 of 15) of ISIS 2302-treated and 20% (1 of 5) of the placebo-treated patients were in remission (Crohn's Disease Activity Index [CDAI] < 150). At the end of month 6, 5 of these 7 ISIS 2302-treated remitters were still in remission, and a 6th patient had a CDAI of 156. Corticosteroid usage was significantly lower (P = 0.0001) in the ISIS 2302-treated patients. These findings were corroborated by significant increases in beta7 and alpha d bearing CD3+ peripheral blood lymphocytes and by decreases in intestinal mucosal ICAM-1 expression during the treatment period. CONCLUSIONS: ISIS 2302 seems to be a well-tolerated and promising therapy for steroid-treated Crohn's disease.