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.

A phase I clinical trial of recombinant DNA gamma interferon.

Recombinant gamma interferon (r-GIFN) demonstrates in vitro and in vivo characteristics that contrast with those of alpha and beta interferons. It has relatively weak antiviral properties, yet relatively potent immunomodulatory effects. A phase I trial was performed with r-GIFN (specific activity 2.6 X 10(6) IU/mg protein), administered as a continuous intravenous (IV) infusion over 24 hours for five days (Cl X 5) and repeated every 28 days. This schedule was chosen based on the short half-life of r-GIFN in animal systems and the in vitro augmentation of biologic effects with continuous exposure to interferons. Twenty-one patients with refractory solid tumors received 46 evaluable courses of therapy. The dose-limiting toxicities included fever, flu-like symptoms, cardiovascular toxicity, and neurotoxicity. The cardiovascular toxicity included hypotension and one episode of cardiac ischemia with chest pain. Neurotoxicity consisted of lethargy and confusion. These toxicities were reversible, and although dose-limiting, occurred sporadically throughout all dosage levels. Mild to moderately severe non-dose-limiting toxicities included nausea and vomiting, leukopenia, and liver function abnormalities. Other infrequent toxicities included hypocalcemia, diarrhea, constipation, and alopecia. The maximally tolerated dose of r-GIFN on this schedule is 0.5 X 10(6) IU/m2/d. Partial responses were seen in one patient with metastatic melanoma and in one patient with renal cell carcinoma. Toxicity and antitumor activity were seen at doses where interferon serum levels could not be detected by radioimmunoassay. In addition, the toxicity and antitumor activity seen were at much lower doses than previously described for shorter infusion schedules of other recombinant gamma interferon preparations. Differences in biologic activity of interferon preparations and/or differences in scheduling may account for this variability. Although this study defines a recommended phase II dose of r-GIFN based on the maximally tolerated dose, the optimal therapeutic index may exist at a lower dosage level.

Treatment of Kaposi's sarcoma with interferon alfa-2b (Intron A).

The activity of the alpha interferons against AIDS-related Kaposi's sarcoma (KS) has been demonstrated in numerous clinical trials. Unfortunately, most reports have involved small patient cohorts and a variety of dosages and schedules of administration. We report here a series of Phase II trials with interferon alfa-2b (Intron A, Schering Corp., Kenilworth, NJ) involving 114 patients using three dose regimens. Patients received 50 X 10(6) IU/m2 intravenously (high dose), 30 X 10(6) IU/m2 subcutaneously (intermediate dose), or 1 X 10(6) IU/m2 subcutaneously (low dose). Clinical responses were seen in all regimens and, overall, 35% of the patients obtained complete or partial remissions. The response rates in the low-, intermediate-, and high-dose groups were 33%, 28%, and 45%, respectively. In addition, high-dose therapy was associated with more rapid time to response. Patients with low-stage (I or II) disease and those who lack B symptoms were more likely to respond to therapy; i.e., response rates for patients without B symptoms were 38%, 44%, and 60% in the low-, intermediate-, and high-dose groups, respectively. Seventy (61%) patients had died at the time of data collection, with a median survival of 15 months. Disease stage and the presence of B symptoms significantly affected mortality. Responders enjoyed significantly longer survival (P less than 0.10) than did nonresponders both overall and when adjusted for disease stage. Interferon alfa-2b was generally well tolerated, although almost all patients experienced flu-like symptoms. No life-threatening toxicities occurred and only six (6%) patients discontinued treatment due to adverse reactions. No significant improvement in immunologic parameters was detected during this study. These studies suggest that, in this disease setting, interferon alfa-2b may be acting through direct antiproliferative effects rather than as an immunomodulator, and higher doses appear to be more effective than very low doses.

Phase I study of recombinant gamma-interferon (rIFN-gamma).

A Phase I study of recombinant gamma-interferon was conducted in 35 patients with advanced malignancy. The schedule was twice weekly administered intravenously. Patients were assigned to six dose levels. The major toxicities were flu-like symptoms and were unrelated to dose. Other adverse reactions, such as myelosuppression, were dose dependent. The addition of a nonsteroidal anti-inflammatory agent did not ameliorate the symptoms at the highest dose level. Antitumor effects occurred in patients with gastric, duodenal, and breast carcinoma.