Robin Bechhofer

Phase 1 Clinical Trial of Recombinant Interleukin-2: A Comparison of Bolus and Continuous Intravenous Infusion

The toxicologic, biologic, and clinical effects of recombinant interleukin-2 (IL-2) were tested in 25 patients with cancer. Escalating doses from 10(3) to 10(7) U/m2 per day were given by either daily bolus injection (BI) or continuous infusion (CI) for 7 consecutive days. Dose-limiting toxicities included a decline in performance status, systolic hypotension, and fever, which reversed promptly with discontinuation of therapy. The maximum tolerated dose of IL-2 by BI for 7 days was 3 X 10(6) U/m2 per day and for CI was 10(6) U/m2 per day. Significant changes in the number, phenotype, and function of circulating peripheral blood lymphocytes occurred at doses greater than or equal to 10(6) U/m2 per day by both administration schedules. With the initiation of therapy, a decline in the number of circulating peripheral blood lymphocytes (PBL) was seen in patients treated by either BI or CI. Additionally, the in vitro cytotoxic activity of these PBL against K562 was markedly decreased. Within 24 h of completing BI or CI, a rebound increase in the number of circulating PBL was seen. The phenotype of the circulating PBL after completion of treatment showed a significant (p greater than or equal to 0.05) increase in the numbers of OKT-3+, OKT-8+, OKT-10+, OK-Ia+, OKM1+, and OKT-11+ for patients treated by CI. Those patients treated by BI had a significant increase in Ia+ and OKT10+ cells. At IL-2 doses greater than or equal to 10(5) U/m2 per day, the PBL obtained following treatment with rIL-2 demonstrated in vitro cytotoxic capacity against K562 target cells that was significantly enhanced over pretreatment levels. This study demonstrates that IL-2 can be given by CI or BI in a non-ICU setting with acceptable dose-dependent toxicity. Upon completion of treatment an increase in the number of activated cells could be detected. Although no clinical responses occurred, the generation of endogenous activated PBL capable of enhanced cytotoxicity is encouraging. Future studies will explore the use of multiple courses of treatment with IL-2 to determine if therapeutic efficacy can be accomplished.

the influence of autologous lymphokine‐activated killer cell infusions on the toxicity and antitumor effect of repetitive cycles of interleukin‐2

Twenty patients with refractory malignancies were treated with a protocol evaluating the addition of ex vivo‐activated autologous lymphokine‐activated killer (LAK) cells to a clinically tolerable interleukin‐2 (IL‐2) regimen (four weekly cycles of human recombinant IL‐2 at 3 × 106 U/m2/day by continuous infusion for 4 days/week). Sixteen patients completed their induction month of therapy, two had a partial response, six had stable disease, and eight had progressive disease. Four patients had clinical toxicity preventing completion of the induction month of therapy, and one of these patients died during therapy. Significant clinical toxities included decreased performance status, weight gain, catheter‐related thromboses, infectious complications, fever, hypotension, and dyspnea or hypoxemia requiring oxygen. Thus, the addition of LAK cell infusions to this IL‐2 regimen did not cause a noticeable change in antitumor response rate but did cause more severe toxicity.

Prolonged Interleukin-2 (IL-2) Treatment Can Augment Immune Activation Without Enhancing Antitumor Activity in Renal Cell Carcinom

Preliminary studies involving small numbers of patients have suggested that interleukin-2 (IL-2) administered by continuous infusion in repetitive weekly cycles using doses of 3 x 10(6) U/M2/day is immunologically active and can induce tumor responses in patients with renal cell carcinoma. This study was designed to examine both the immunological and clinical effects of prolonged infusion IL-2 given by repetitive weekly cycles; first at moderate doses for 4 weeks as an impatient followed by lower doses of IL-2 for up to 5 months. Prolonged IL-2 treatment was investigated because previous studies revealed that patients had a return to their baseline immune status within 4 weeks after completing IL-2 treatment. Twenty-five patients (including 18 with renal cell carcinoma) were treated with one of two regimens utilizing IL-2 as sole therapy. These regimens were designed to induce augmented and prolonged immune activation based upon in vitro and in vivo data. Though patients on both arms of the study demonstrated sustained lymphocytosis, increase in numbers of natural killer cells, and induction of lymphokine-activated killer activity with prolonged IL-2 administration, only 1 out of the 18 patients with renal cell carcinoma demonstrated a sustained partial antitumor response to therapy. Furthermore, several patients demonstrated profound immune activation, without any evidence of tumor regression. The lack of clinical responses in these patients showing marked activation of LAK cytotoxicity suggests that other variables must also influence the likelihood of antitumor effects for patients receiving IL-2 therapy.

Serum CD25 levels during interleukin-2 therapy : dose dependence and correlations with clinical toxicity and lymphocyte surface sCD25 expression

Summary Using an enzyme-linked immunosorbent assay (ELISA), we have measured serum levels of a soluble form of the p55 subunit of the interleukin-2 receptor complex, soluble CD25 (sCD25), at regular intervals in the sera of 51 pediatric and adult cancer patients receiving recombinant human interleukin-2 (IL-2). The IL-2 was administered in repetitive weekly cycles alone or in combination with lymphokine-activated killer (LAK) cells. Levels of CD25 correlated with clinical toxicities reflected by nadir blood pressures, percentages of weight gained, and minimum Karnofsky performances during IL-2 therapy. Coadministration of autologous in vitro activated LAK cells together with IL-2 did not significantly affect the pattern of sCD25 release relative to administration of IL-2 alone. Examination of sCD25 release in response to different doses of IL-2 revealed a statistically significant dose effect of IL-2 on the sCD25 levels in patient sera. In addition, the level of sCD25 in patient sera also correlated strongly with expression of CD25 on the surface of peripheral blood lymphocytes (PBL) obtained from patients following IL-2 therapy. These studies demonstrate the utility of the sCD25 ELISA as a clinical tool for monitoring patients on treatment regimens that include IL-2.

A pilot phase II trial of continuous-infusion interleukin-2 followed by lymphokine-activated killer cell therapy and bolus-infusion interleukin-2 in renal cancer.

Nine patients with metastatic renal cell carcinoma were entered into a pilot protocol including a 4-week regimen utilizing human recombinant interleukin-2 (IL-2) and in vitro lymphokine-activated killer (LAK) cells. The regimen included 2 weeks (4 days of treatment and 3 days of rest/week) of continuous-infusion (c.i.) IL-2 at 3 x 10(6) U/m2/day, followed by two leukaphereses. LAK cells were cultured in vitro for 48 to 72 h and administered as a single infusion, followed by 9 days of bolus i.v. injections of 10(6) U IL-2/m2/dose, given every 8 hours (t.i.d.). The average (+/- SD) number of LAK cells infused per patient was 7.2 x 10(10) (+/- 3.5 x 10(10)). One patient showed > 50% shrinkage of tumor (lung + renal bed recurrence). Toxicity was similar to that encountered in other studies using similar IL-2 doses and LAK cells and consisted of fever, hypotension, fluid retention, and reversible renal insufficiency. These results indicate that the 2 weeks of IL-2 c.i. provided conditions enabling the harvest of large quantities of mononuclear cells from the peripheral blood of patients; this could be useful for future trials requiring the use of in vitro activated lymphocytes. Nevertheless, these pilot data suggest that this regimen of prolonged t.i.d. IL-2 administration after the LAK infusion does not seem to generate any improvement in antitumor effects from those obtained using other LAK + IL-2 regimens.

Reports to Independent Data Monitoring Committees: An Appeal for Clarity, Completeness, and Comprehensibility

Background: Organizations presenting reports to independent data monitoring committees (IDMCs) should present data in a way that facilitates the ability of the IDMC to make informed judgments about the trial. Methods: This paper reviews reports to IDMCs and suggests approaches an independent statistical reporting group (ISRG) might take to prepare clear, complete, and comprehensible reports. Results: Sensible reporting by an ISRG and informed decision making by an IDMC require a productive partnership between the quantitative and clinical disciplines involved in a clinical trial. IDMC reports differ in structure and purpose from clinical study reports that summarize data at the end of a trial. The ISRG must have intellectual independence, recognizing that although the sponsor may be paying the bills, the ISRG is responsible to the IDMC. Ideally, it should have access to all data from the trial and should be capable of responding to requests from the IDMC without the sponsor’s specific permission. The ISRG and sponsor must understand the differences between clean data at the end of the trial and data collected during the trial. To perform its role most effectively, the ISRG must collaborate with sponsor and IDMC clinicians to become conversant with the disease area, the product’s mechanism of action, and the clinical relevance of important outcome measures. Conclusions: An IDMC is best served by an independent ISRG that will prepare clear, complete, and comprehensible reports. Given the complexities of interim data and IDMC requirements, the ISRG must be an active and informed participant in the monitoring process.