248 Growth factors in combination: Phase I study of dose intensified carboplatin (CB), cyclophosphamide (CT) and etoposide (VP) in patients (PTS) with advanced, refractory cancer

This phase I study was designed in order to verify the toxicity of CB. CTX, VP given at high doses, in combination with GCSF alone or GCS and GMCSF given sequentially. The two lymphokines, with different properties, might have their ideal integration in the sequential administration. A group of 10 heavily pretread patients (PTS) with stage IV disease (2 breast cancer, 2 small cell and 1 non small cell lung cancer, 1 sarcoma, 1 colorectal cancer, 1 ependymoblastorna, 1 signet-ring cell bladder cancer, 1 neuroendocrine prostate cancer) were enrolled into the study between August and September 1994. Median (M) PS (ECOG) was 1, M age 41 years (22–65). Previous treatments: 7 PTS had surgery, 4 PTS had radiotherapy, all PTS had received previously a median of 4. 5 chemotherapy courses (4–12). CB-CTX-VP combination was administered over 3 days. Each patient, received two courses of the same CT, followed, randomly, either by 14 days of GCSF (arm A) or by 7 days of GCSF and 7 days of GMCSF (arm B) with cross over in the second CT course. Both growth factors were given sq at the dose of 5 μg/kg/day. CB dose was calculated according to Calvert et al. (JCO 1989,7:1748) and expressed with the area under the concentration versus time curve (AUC). All patients received an outpatient treatment. The maximum tolerated doses of CTX and Vp, found in a previous work (Ann Oncol 1994, 5:90,), were, respectively, 1500 and 400 mg/m2, while CB doses ranged from 5 to 8 AUC. Twenty chemotherapy courses over 20 are evaluable. Absolute neutrophil count (ANC) < 1000 μL for 54 days in arm A versus 68 days in arm B (P = 0.02); platelets (PLT) count < 25.000 μL: 57 days arm A versus 30 days in arm B (P = 0.03); days of hospitalisation 35 in arm Aversus 16 in arm B (P = 0.75); platelets transfusion: 107 Vs 58 (P = 0.02); PRBCS 15 vs 5 (P = 0.25). No treatment related death occurred. At the present time, eight patients had responses and are alive. These data indicate that dose intensified CT may be delivered safely; GCSF alone shortens days of neutropenia, the combination of the 2 cytokines shortens the time of thrombocytopenia and decreases the number of platelets transfusions.