Polyriboinosinic-polyribocytidylic acid, stabilized with poly-l-lysine and carboxymethylcellulose [poly(ICLC)], resists hydrolysis by primate serum (unlike the parent compound), induces high levels of serum interferon, and is effective in acute viral infections of subhuman primates. In a Phase I clinical trial, poly(ICLC) was given i.v. in 15 daily doses of 0.5 to 27.0 mg/sq m to 19 patients with various solid tumors and six patients with acute leukemia (ages 1 to 65). At least three complete trials were conducted at each of six dose levels. Toxic reactions included fever (in 100% of trials), nausea (44%), hypotension (28%), thrombocytopenia and leukopenia (68%), erythema (12%), and polyarthralgia plus myalgia (16%). Hypotension and arthralgia-myalgia related to dose level and/or magnitude of interferon induction, but other toxic manifestations did not. Poly(ICLC) induced significant serum interferon levels in 76% of trials, and the correlation between dose and peak interferon titer was linear. The maximum tolerated dose for all patients at a given drug dose was 12 mg/sq m; at this dose, the mean peak interferon titer was 1940 reference units/ml. At 18 mg/sq m, the mean peak interferon titer was 4473 reference units/ml, but myalgia and arthralgia were severe in at least one-half of the patients, and most had significant hypotension. At 27 mg/sq m, one patient had acute renal failure. At high doses, i.v. poly(ICLC) also induces interferon in the cerebrospinal fluid. One patient, a child with acute lymphocytic leukemia, had a complete remission after treatment with this compound. While this response cannot be assigned unambiguously, further trials in leukemia are warranted. Moreover, our observation that poly(ICLC), at a tolerable dose, is the first consistent inducer of high serum interferon levels in humans suggests that it should be studied in certain human viral infections.

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