Phase I trial of biochemotherapy with cisplatin, temozolomide, and dose escalation of nab-paclitaxel combined with interleukin-2 and interferon-α in patients with metastatic melanoma

Abstract

The primary objective of this study was to determine the safety, toxicity, and maximum tolerated dose of nanoparticle albumin-bound (nab)-paclitaxel as part of biochemotherapy for metastatic melanoma and to determine whether substituting nab-paclitaxel for less potent agents could increase response rates and duration. Treatment consisted of intravenous cisplatin (20 mg/m2) on days 1–4, oral temozolomide (250 mg/m2) on days 1–3, subcutaneous interferon-α (5 × 106 IU/m2) on days 1–5, and continuous intravenous interleukin-2 (9 × 106 IU/m2) for 96 h on days 1–4. A standard 3 + 3 dose escalation method was used; the nab-paclitaxel starting dose was 100 mg/m2 on day 1 and 70 mg/m2 on day 5. The treatment cycle was repeated every 3 weeks and toxicity was assessed weekly. Ten patients were enrolled. Dose-limiting toxicities included diarrhea, transaminasemia, and neutropenia. The maximum tolerated dose was not identified because the nab-paclitaxel dose on day 1 at the lowest planned dose (80 mg/m2) caused dose-limiting toxicity in two of five patients. Of the nine patients who were evaluable for response, five had a partial response. The median time to disease progression was 5.30 months and the median overall survival was 8.73 months. Six patients developed central nervous system metastasis at a median of 5.33 months after treatment initiation. Biochemotherapy including nab-paclitaxel according to the doses and schedule regimen used in the present study has significant toxicity. Substituting dacarbazine with temozolomide did not prevent central nervous system metastasis in patients with metastatic melanoma.

Targeting mitosis‐regulating genes in cisplatin‐sensitive and ‐resistant melanoma cells: A live‐cell RNAi screen displays differential nucleus‐derived phenotypes

“…Among others, we identified some prominent and well described genes as disrupters of melanoma tumor cell mitosis for both cisplatin‐sensitive and ‐resistant cells. While cisplatin is not used as single agent in the chemotherapy of disseminated melanoma, it has been contained in numerous combinational therapeutic approaches [30–34]. The cytotoxic effect of cisplatin involves active uptake into cells and subsequent binding to the DNA.…”

Interferon-α versus interleukin-2 in Chinese patients with malignant melanoma

“…As first-line therapy, patients of IFN-α group received subcutaneous 9×10 6 IU/m 2 IFN-α at every 21 days for 4 months 1 . Patients of IL-2 group received continuous (over 96 h) intravenous 9×10 6 IU/m 2 IL-2 at every 21 days for 4 months 14 .…”

The era of bioengineering: how will this affect the next generation of cancer immunotherapy?

“…Despite this, clinical studies in combination with immunotherapy regimens are only slowly starting to emerge. One recent Phase I study investigated the combination of nab -paclitaxel with immunotherapy (co-administration of soluble IL-2 and IFN-α) in metastatic melanoma, but the study failed to identify the maximum tolerated dose due to recorded toxicity at the lowest concentration tested and also the limited number of patients enrolled (10) [ 53 ]. On the other hand, a Phase Ib study in metastatic triple-negative breast cancer patients confirmed the safety and the therapeutic benefit of a combination of a checkpoint inhibitor (anti-PD-L1: atezolizumab) with nab -paclitaxel, setting the basis for an ongoing Phase III clinical trial [ 54 ].…”