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Biomedical subjects

L M Itri

Publications and source records attributed to L M Itri.

At least 37 records · Page 2Linked to original sources
PubMed1988

Treatment of advanced squamous cell carcinoma of the head and neck with isotretinoin: a phase II randomized trial.

Retinoids, the analogs of vitamin A, are active in vitro and in vivo against squamous cell carcinoma in animals and against certain epithelial precancers and cancers in humans. These data led us to design a prospective, multi-institutional, randomized phase II trial of isotretinoin in advanced head and neck squamous cell carcinoma. We randomly assigned 40 patients to receive isotretinoin or methotrexate, the best-studied and most active single agent for this disease. Overall, the study patients had extremely poor prognoses, i.e., low performance statuses and recurring disease after surgery and/or irradiation. Three objective responses (16%), including one complete response, occurred in the 19 evaluable isotretinoin-treated patients. Only one minor response (5%) occurred in the methotrexate-treated group. Toxicity occurred with both drugs, but was manageable and never life threatening in the retinoid group. These results and the established activity of retinoids in oral leukoplakia (a precursor of head and neck cancer) indicate the need for further study of this class of drugs in head and neck cancer.

Adult↗
PubMed1988

Recombinant interferon alfa-2a in metastatic renal cell carcinoma: assessment of antitumor activity and anti-interferon antibody formation.

Twenty-one patients with advanced, measurable, renal cell carcinoma (RCC) were administered recombinant interferon alfa-2a (rIFN-alpha 2a) (Roferon-A; Roche Laboratories, Nutley, NJ) intramuscularly beginning at 3 x 10(6) units and escalating to 36 x 10(6) units, 5 d/wk for a total induction period of 14 weeks. rIFN-alpha 2a antibody production was measured using an enzyme immunoassay (EIA). Those sera found to be positive for presence of antibody by the EIA were tested for the presence of neutralizing antibodies (NA) by an antiviral neutralization bioassay (ANB). All patients were evaluable for toxicity, and 19 were evaluable for response and for incidence of antibody formation. Five patients (26%; 95% confidence interval, 6% to 46%) had complete responses (CR) or partial responses (PR) with a median duration of 283 days. An additional ten patients (53%) had minor tumor regressions with a median duration of 86 days. Fifty-one percent of evaluable patients are alive at 18.6 months. Antibodies to rIFN-alpha 2a as measured by the EIA, were detected in 12 (63%) patients. NA were measured in the serum of six (50%) of those EIA-positive patients. Overall, six of 19 patients (32%) developed NA. Median time to the development of antibody as measured by EIA or NA was 8 and 14 weeks, respectively. Median NA titer was 1,200 IFN neutralizing U/mL. NA-positive and -negative patients had a median duration of response of 13.7 v 9.9 months, and survival of greater than 21.3 v 18.3 months, respectively. Clinical toxicity was mild and not therapeutically limiting. Autoantibody production (ANA, rheumatoid factor [RF], Coombs' direct/indirect) occurred in both NA-positive and -negative patients. The clinical significance of the antibodies to rIFN-alpha 2a and the associated autoantibody formation remain unclear; however, presence of antibody was not associated with adverse clinical sequelae.

Adult↗
PubMed1988

Anti-interferon antibodies: a perspective.

Clinical trials with both recombinant and natural alpha and beta interferons have shown that patients may develop neutralizing antibodies to these proteins. Differences in trial design and in the sensitivity of the assays used to measure antibodies have made it difficult to evaluate the factors that influence antibody formation and the effects of these antibodies on clinical results. In several trials, neutralizing antibodies to the recombinant alpha interferons were temporally associated with decreased response to therapy in a few patients, particularly those with B-cell disorders; however, these antibodies had no effect on clinical outcome in other trials. Long periods of treatment and/or higher doses of interferons, both of which contribute to increased cumulative doses of protein, generally are associated with a higher incidence of antibody formation. The source of protein, the route of administration, and the underlying disease also may influence the development of antibodies. Further studies must assess the role of each of these factors carefully to determine which patients are most likely to develop neutralizing antibodies so that clinical effects can be quantitated and appropriate management can be recommended.

Antibody Formation↗
PubMed1987

Three consecutive phase II studies of recombinant interferon alfa-2a in advanced malignant melanoma. Updated analyses.

In three consecutive Phase II trials of recombinant interferon alfa-2a (rIFN alfa-2a; Roferon-A Hoffmann-La Roche, Nutley, NJ) involving 96 patients with advanced malignant melanoma, an overall response rate of 22% was observed. For all study participants, the median time to disease progression was 1.7 months, and the median survival was six months. Most regressions occurred within one month of commencing therapy, were usually limited to soft tissue metastases, and were transient. However, responses in three patients were long term, lasting 32+, 36+, and 41+ months. A thrice weekly intramuscular dose of 50 x 10(6) U/m2 produced an intolerable flulike illness concomitant with a median weight loss of 5.6 kg. The addition of cimetidine to the same dose in 35 patients was of no therapeutic value. A dose of 12 x 10(6) U/m2 produced clinically acceptable toxicities, and a median weight loss of 2.1 kg. There was no apparent dose response relationship, nor were there any obvious sequelae from antibody formation to interferon alfa-2a. As single agent therapy in malignant melanoma, interferon alfa-2a was only marginally useful in most patients. Nevertheless, combination regimens of this agent with cytotoxic agents, alternative molecular species of interferon, and lymphokines, notably tumor necrosis factor, offer a conceptually intriguing dimension in the design of future clinical trials.

Adjuvants, Immunologic↗
PubMed1987

Incidence and clinical significance of neutralizing antibodies in patients receiving recombinant interferon alfa-2a by intramuscular injection.

More than 1600 patients with neoplastic disorders have received recombinant human interferon alfa-2a (Roferon-A, Hoffmann-La Roche, Nutley, NJ) as part of ongoing or completed clinical trials. In this report, the efficacy of interferon alfa-2a therapy was compared with the incidence of antibodies to this interferon in 617 patients who received the drug by intramuscular administration. Antibody measurements were performed using a highly sensitive enzyme immunoassay, and an interferon antiviral neutralization bioassay. Partial or complete remission occurred in 28% (43 of 152) of the antibody-positive patients, and in 24% (112 of 465) of the antibody-negative patients (P = 0.33). The highest incidence of antibody formation occurred among patients with renal cell carcinoma and acquired immune deficiency syndrome (AIDS)-related Kaposi's sarcoma (44% and 34%, respectively). Both the duration of treatment and length of survival were significantly longer for antibody-positive than for antibody-negative patients. No significant intergroup differences emerged for response rates or for time to onset or duration of therapeutic response. When results from the above assays were compared to those used for the detection of antibodies to recombinant interferon alfa-2b (Intron A, Schering-Plough Inc., Kenilworth, NJ), the immunoradiometric assay method was determined to be seriously deficient for determination of antibody incidence. This decreased assay sensitivity may account for the reportedly lower incidence of antibodies to recombinant alfa-2b interferon.

AIDS-Related Opportunistic Infections↗
PubMed1986

Recombinant leukocyte A interferon (rIFN-alpha A) in the treatment of disseminated malignant melanoma. Analysis of complete and long-term responding patients.

Ninety-six patients with disseminated malignant melanoma received thrice weekly intramuscular injections of leukocyte A recombinant interferon (rIFN-alpha A, Roferon-A, Hoffmann La Roche) at doses of 12 X 10(6) U/m2 or 50 X 10(6) U/m2 with or without cimetidine as an immunorestorative agent. Four patients, two with prior chemotherapy, demonstrated either a complete response (3 months, soft tissue metastasis) or exceptionally durable response durations (months) of 29+ (soft tissue; lung lesion), 31+ (soft tissue), and 35+ (soft tissue; liver lesions). None of these patients had particularly characteristic clinical parameters. As noted previously, using chemotherapy, a small proportion of patients with advanced malignant melanoma, despite prior therapy, may achieve prolonged objective regression with rIFN-alpha A.

Adult↗
PubMed1986

13-cis-retinoic acid in the treatment of oral leukoplakia.

13-cis-Retinoic acid has been reported to be effective in treating oral leukoplakia. We randomly assigned 44 patients with this disease to receive 13-cis-retinoic acid (24 patients) or placebo (20), 1 to 2 mg per kilogram of body weight per day for three months, and followed them for six months. There were major decreases in the size of the lesions in 67 percent (16 patients) of those given the drug and in 10 percent (2 patients) of those given placebo (P = 0.0002); dysplasia was reversed in 54 percent (13 patients) of the drug group and in 10 percent (2 patients) of the placebo group (P = 0.01). The clinical response to the drug correlated with the histologic response in 56 percent (9 of 16) of the patients evaluated. Relapse occurred in 9 of 16 patients two to three months after treatment ended. The toxic effects of the drug were acceptable in all but two patients. Cheilitis, facial erythema, and dryness and peeling of the skin were common; conjunctivitis and hypertriglyceridemia also occurred. All adverse reactions could be reversed by reducing the dose or temporarily discontinuing the drug. We conclude that 13-cis-retinoic acid, even in short-term use, appears to be an effective treatment for oral leukoplakia and has an acceptable level of toxicity.

Aged↗
PubMed1986

Safety and tolerance of recombinant interferon alfa-2a (Roferon-A) in cancer patients.

Recombinant interferon alfa-2a (Roferon-A, Hoffmann-La Roche Inc., Nutley, NJ) has been evaluated in clinical trials of more than 1300 patients with a broad spectrum of oncologic disease. Patients with either solid tumors or hematologic malignancies were treated with daily or three-times-weekly intramuscular injections for induction periods ranging from 8 to 16 weeks. Doses ranged from 1 X 10(6) units to 124 X 10(6) units per injection. When administered in low daily doses (approximately 3 X 10(6) units), Roferon-A was well tolerated, and dose attenuation was rarely required. Change to three-times-weekly treatment regimen at the same dose was usually sufficient to control toxicity when it occurred in this group of low-dose patients. Those patients receiving higher doses frequently required dose attenuation to 50% of the starting dose to improve clinical tolerance. Virtually all patients treated with Roferon-A experienced some degree of acute toxicity manifested as fever, chills, myalgia, and/or headache. These reactions usually occurred with initial dosing and frequently improved spontaneously with continued administration of the drug. Acetaminophen pretreatment was generally useful in ameliorating these symptoms. Common adverse experiences occurring after repeated dosing included fatigue, anorexia, and weight loss. Serious adverse reactions including cardiovascular and neurologic toxicity have occurred infrequently, primarily at higher doses. Hematologic toxicity and elevations in liver function parameters were also observed, but rarely required dose attenuation. Adverse effects were usually reversible after dose reduction or discontinuation of therapy. Approximately 27% of all patients developed antibodies to rHuIFN-alpha 2A during treatment. No adverse clinical sequelae have been associated with antibody development to date.

Adolescent↗
PubMed1986

Phase I study of a combination of recombinant interferon-alpha and recombinant interferon-gamma in cancer patients.

Combinations of interferon-alpha and interferon-gamma demonstrate synergistic antiviral and anti-proliferative activity in vitro. Therefore, we initiated a clinical study of combination interferon therapy in humans. Eighteen patients with metastatic solid tumors received daily intramuscular (IM) injections of recombinant interferon-alpha-A (IFN alfa-2a, Roferon-A; Hoffman-LaRoche, Nutley, NJ) and recombinant IFN-gamma (rIFN-gamma) for 6 weeks. The dose levels were 0.5, 1.0, 2.0, and 5.0 X 10(6) U/m2/d of each interferon. A minimum of two patients were entered sequentially at each dose level. Fever, chills, fatigue, and a greater than or equal to 50% drop in granulocyte counts were observed at all doses. Severity of symptoms corresponded to increasing dose levels. In contrast to the tachyphylaxis to these symptoms that usually develops in patients treated with the individual interferons, many patients on this study experienced persistent fever and worsening fatigue over 6 weeks. The maximum tolerated dose was 1 X 10(6) U/m2/d of each interferon. One patient with renal-cell carcinoma achieved a partial remission (duration, 3 months). Enzyme-linked immunoassay analysis in all four patients for whom complete data were available revealed that peak blood levels of IFN alfa-2a on day 22 were about tenfold higher than on day 1. Because of the possibility of cumulative toxicity, the recommended starting dose for further studies is 0.5 X 10(6) U/m2/d of each interferon, with escalation to 1.0 X 10(6) U/m2/d after 1 month if tolerance is acceptable. Phase II investigations to explore the antitumor efficacy of this regimen are planned.

Adult↗
PubMed1986

Clinical trial of recombinant leukocyte A interferon as initial therapy for favorable histology non-Hodgkin's lymphomas and chronic lymphocytic leukemia. An Eastern Cooperative Oncology Group pilot study.

Twenty patients with disseminated favorable histology non-Hodgkin's lymphomas (16 patients) or chronic lymphocytic leukemia (four patients) who had not received previous chemotherapy were treated with recombinant leukocyte A interferon (IFL-rA) (Hoffmann-La Roche, Nutley, NJ). Treatment was administered in a moderate dose (12 X 10(6) U/m2) by intramuscular (IM) injection three times weekly for 8 weeks, followed by weekly maintenance therapy for an additional 16 weeks in patients responding to therapy. Five patients with stable disease at 8 weeks received four additional weeks of three-times-weekly treatment at an escalated dose (25 X 10(6) U/m2). Interferon was tolerated without severe toxicity by most patients, although treatment was discontinued prematurely due to side effects in four patients. Objective tumor responses (one complete response [CR] and six partial responses [PRs]) were seen in seven of 16 patients with lymphoma (44%). One of four patients with chronic lymphocytic leukemia also experienced a PR. Median time-to-progression from initiation of therapy among responding patients was 26 + weeks (range, 7 + to 84 + weeks). This study has demonstrated single agent antitumor activity of IFL-rA given in a tolerable outpatient dosage regimen in patients with advanced favorable histology non-Hodgkin's lymphomas, and serves as a basis for further trials of IFL-rA combined with chemotherapy as initial therapy for such patients in the future.

Adult↗
PubMed1986

Phase II trials of recombinant leukocyte A interferon in disseminated malignant melanoma: results in 96 patients.

Ninety-six patients with advanced malignant melanoma received thrice weekly im recombinant leukocyte A interferon (Roferon-A) in three consecutive phase II trials utilizing doses of 12 X 10(6) U/m2, 50 X 10(6) U/m2, and 50 X 10(6) U/m2 plus cimetidine. The overall response rate was 22%, with median times to disease progression and survival of 3.9 and 11.3 months, respectively. For all study participants, the median times to disease progression and survival were 1.5 and 5 months, respectively. Most regressions occurred within the first month of treatment and were predominantly in soft tissue, although three patients are responding 2-3 years after onset of treatment. The most noteworthy toxic effects included a flu-type illness, anorexia, and fever (38.3-39.4 degrees C). The median weight loss was 2.1 kg on the low-dose regimen and 5.6 kg on the high-dose program. Recombinant leukocyte A interferon in the dosages and schedule that we used has definite but limited efficacy for patients with disseminated malignant melanoma.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1985

Phase II study of recombinant leukocyte A interferon (IFN-rA) plus cimetidine in disseminated malignant melanoma.

Thirty-five eligible patients with disseminated malignant melanoma received intramuscular recombinant leukocyte interferon (IFN-rA), 50 X 10(6) U/m2 three times weekly (TIW) for an intended duration of 12 weeks concomitant with daily oral cimetidine, 1,200 mg/d in four divided doses. For all study participants, the median survival time was six months. Among 21 "good risk" patients (performance score [PS] 0, 1 and no prior chemotherapy), we observed seven partial regressions (33%). Six patients had stability of disease (29%), seven had immediate disease progression, and one discontinued treatment after two doses without tumor evaluation due to side effects. Times to disease progression of five patients with regressions of soft-tissue disease were 2.1, 3.3, 3.5, 3.7, and 4.3 months. Two patients had partial regressions of lung nodules for 2.0 and 3.8 months. We observed one regression among 14 "poor risk" patients (PS 2, 3, or prior chemotherapy). A 46-year-old woman with prior treatment had a partial regression of soft-tissue disease for 4.1 months. Four "poor risk" patients achieved disease stability, and nine progressed immediately. Leukopenia (WBC count less than 4,100/microL) affected 21 (66%) of 32 patients with WBC count data. The median count was 3,100/microL; range, 1,300 to 8,400/microL. We detected two cases of mild thrombocytopenia (100,000 and 120,000/microL). Other noteworthy toxicities included moderate-to-severe nausea (34%), anorexia (63%), and fatigue (80%). All patients experienced myalgias. Twenty patients had dosage decreases during the first cycle, and 14 of the 16 patients remaining on study after the first cycle required dosage reductions. The overall response rate is similar to our prior studies with IFN-rA as a single agent using TIW doses of 50 X 10(6) U/m2 and 12 X 10(6) U/m2 among 31 and 30 patients, respectively.

Administration, Oral↗
PubMed1984

Phase II study of low-dose recombinant leukocyte A interferon in disseminated malignant melanoma.

Thirty patients with disseminated malignant melanoma received intramuscular recombinant leukocyte A interferon (rIFN-alpha A), 12 X 10(6) U/m2, three times weekly for a planned treatment duration of three months. This dose was selected in view of our prior phase II data indicating that 50 X 10(6) U/m2 three times weekly produced excessive toxicity. In this current trial we observed three objective partial regressions (20%) among the 15 better-risk patients (performance score 0, 1, and no prior chemotherapy) with times to disease progression of 1.9, 9.6, and 12.9+ months. There were also three regressions (one complete and two partial) among the 15 poor-risk patients (performance score 2, 3, or prior chemotherapy) with progression times of 3, 3.2, and 9.6+ months. For all patients, the median survival time was 4.2 months. One half of the patients were observed to have progressive disease within one month of commencing treatment. Responding metastatic lesions were limited to soft tissue, although one patient also had a partial response of a lung nodule. The most substantial toxicities were moderate-to-severe myalgias (27%), nausea (33%), anorexia (47%), and fatigue (50%). Among the 22 patients with weight loss, the median was 2.3 kg (range, 0.6 to 8.4 kg). Hematologic and hepatic toxicity was transient and of little clinical significance. Our study indicates that rIFN-alpha A in the dose and schedule that we used is clinically tolerable and has antitumor activity in malignant melanoma. The response rate was similar to results observed in our previous study of a higher dose regimen.

DNA, Recombinant↗