IL-2 Based Combination Therapy of Malignant Disease: Summary of the Phase I Experience at the Cleveland Clinic
We have performed Phase I trials of rIL-2 in combination with IFNα or doxorubicin (DOX), based upon the independent activity of these agents and preclinical evidence of therapeutic synergy. In a Phase I trial of the combination of doxorubicin (DOX) and rIL-2, myelosuppression prevented dose escalation beyond the MTD of DOX 40 mg/m2 IV bolus day 1 and rIL-2 3.0 MU/m2/24 hr IV on days 2–5, 9–12, and 16–19. Significant increases in peripheral blood NK and LAK precursor activities were observed, but no clinical responses were produced in this patient population with largely gastrointestinal malignancies. In other Phase I studies, four week cycles of rIL-2 given by intravenous (IV) bolus injection three times weekly (TIW) have been administered in combination with rHuIFNα2a given intramuscularly (IM) TIW. With aggressive supportive care, the Maximum Tolerated Dose (MTD) of rIL-2 that could be given with rHuIFNα2a 10 MU/m2 IM TIW was 22.0 x 106 BRMP Units (MU)/m2 IV TIW. Dose limiting toxicities were CNS, pulmonary and cardiovascular. When given with rHuIFNα2a 10.0 MU/m2 TIW, the MTD of infusion rIL-2 was 3.0 MU/m2/24 hr x 5 days, weekly x 4. We have also treated pts with RCC and MM in Phase II trials of rIL-2 3.0 MU/m2/24 hrs D1–4 and rHuIFNα2a 5.0 MU/m2 SQ D1–4. Overall, 3/7 pts with RCC treated with infusion schedule rIL-2 and rHuIFNα2a have responded in our Phase I study, as opposed to 3/33 pts with RCC treated with bolus schedule rIL-2 and rHuIFNα2a. Of pts with MM, 6/23 pts have responded to bolus schedule rIL-2 and rHuIFNα2a while 0/3 have responded to infusion schedule rIL-2 with rHuIFNα2a in our Phase I studies. We have also entered patients on multi-center Phase II studies utilizing a somewhat less dose-intense schedule of infusion schedule rIL-2 and rHuIFNα2a. Among patients entered on these trials from the Cleveland Clinic, 3/11 pts with RCC have responded, while 2/10 pts with MM have responded. Further studies of the mechanisms by which responses are mediated are needed if IL-2 based therapies are to be improved.
KeywordsRenal Cell Carcinoma Maximum Tolerate Dose Metastatic Renal Cell Carcinoma Unacceptable Toxicity Lower Dose Level
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