Clinical and Biological Effects of Recombinant Interferon-β Administered Intravenously Daily in Phase I Trial

Interferons manifest diverse immunomodulatory and antiproliferative characteristics. Since their spectrum of toxicities includes primarily fatigue and anorexia rather than the myelosuppression concomitant with cytotoxic therapies, it is conceptually appealing to combine both modalities. We conducted a phase I trial among 18 patients using the combination of leukocyte A recombinant interferon (IFN-rA) and BCNU. The intramuscular (IM) IFN-rA dose for the initial 12 patients was 12 X 10(6) U/m2 three times a week for an anticipated duration of 12 weeks. Among these patients, we escalated the monthly intravenous (IV) BCNU dose from 50 mg/m2 to 150 mg/m2. Six subsequent patients received IFN-rA 12 X 10(6) U/m2, days 1 to 3, and BCNU 150 mg IV on day 3 of each monthly cycle. Dose-limiting toxicities from both regimens were fatigue and myelosuppression. We recognize the limitation of small sample sizes. Nevertheless, in the absence of a significant number of life-threatening toxicities, it appears that near maximal doses of BCNU and concomitant IFN-rA can be administered with safety in an outpatient setting.

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Phase I trial of bortezomib daily dose: Safety, pharmacokinetic profile, biological effects, and early clinical evaluation in patients with advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.15_suppl.2623 ◽

2014 ◽

Vol 32 (15_suppl) ◽

pp. 2623-2623

Author(s):

Rastislav Bahleda ◽

Marie-Cécile Le Deley ◽

Apexa Bernard ◽

Shalini Chaturvedi ◽

Anas Gazzah ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Clinical Evaluation ◽

Phase I Trial ◽

Biological Effects ◽

Pharmacokinetic Profile ◽

Advanced Solid Tumors ◽

Daily Dose

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A multicenter phase I trial of combination therapy with interferon-β and temozolomide for high-grade gliomas (INTEGRA study): the final report

Journal of Neuro-Oncology ◽

10.1007/s11060-011-0529-1 ◽

2011 ◽

Vol 104 (2) ◽

pp. 573-577 ◽

Cited By ~ 26

Author(s):

Toshihiko Wakabayashi ◽

Takamasa Kayama ◽

Ryo Nishikawa ◽

Hiroshi Takahashi ◽

Naoya Hashimoto ◽

...

Keyword(s):

Combination Therapy ◽

Phase I ◽

Phase I Trial ◽

Final Report ◽

High Grade ◽

Interferon Β ◽

Multicenter Phase ◽

High Grade Gliomas

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A phase I trial with recombinant interferon γ (Roussel UCLAF) in advanced cancer patients

Cancer Immunology Immunotherapy ◽

10.1007/bf01741727 ◽

1990 ◽

Vol 32 (1) ◽

pp. 67-70 ◽

Cited By ~ 8

Author(s):

François Boue ◽

Zulay Pastran ◽

Marc Spielmann ◽

Thierry Le Chevalier ◽

Rosana Subirana ◽

...

Keyword(s):

Phase I ◽

Cancer Patients ◽

Advanced Cancer ◽

Phase I Trial ◽

Interferon Γ ◽

Advanced Cancer Patients ◽

Recombinant Interferon

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Phase I trial of a sequence-specific combination of the HDAC inhibitor, valproic acid (VPA), and the topoisomerase II inhibitor, epirubicin, in advanced solid tumors: Clinical results and correlative studies

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.3068 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 3068-3068 ◽

Cited By ~ 4

Author(s):

P. N. Munster ◽

D. C. Marchion ◽

E. Bicaku ◽

M. L. Schmitt ◽

B. Padilla ◽

...

Keyword(s):

Phase I ◽

Histone Acetylation ◽

Solid Tumors ◽

Phase I Trial ◽

Biological Effects ◽

Median Number ◽

Minor Response ◽

Specific Combination ◽

Topo Ii ◽

Tumor Types

3068 Background: Multiple lines of evidence indicate that histone deacetylase inhibitors (HDACi) potentiate topoisomerase (topo) inhibitors. The HDACi-induced histone acetylation and chromatin modulation facilitates DNA access and target recruitment for topo II inhibitors. Methods: This Phase I trial explored a sequence-specific combination of VPA and epirubicin in solid tumors. A VPA loading dose and 6 oral doses (q12h) were given prior to epirubicin in 3-week cycles. Histone acetylation and topo II expression were evaluated in pre-and post-VPA peripheral blood mononuclear cells and tumor samples. Results: To date, 42 patients [median age 53 (39–78)] have been treated in 12 cohorts: IV VPA loading (mg/kg)/epirubicin (mg/m2): 15/75, 30/75, 45/75, 60/75, 75/75 and 75/100, oral loading: 75/100, 90/100, 100/100, 120/100, 140/100 and 160/100. Tumor types included: breast (10), melanoma (11), lung (6), sarcoma (2), GYN (2), GI (5) and others (6). Dose-limiting toxicities included somnolence (1) and neutropenia (1). No exacerbation of epirubicin-related toxicities was observed. Objective responses were seen across different tumor types in anthracycline-resistant and -refractory tumors, despite a median number of 3 (0–6) prior regimens: Partial response; 7/37 (19%), stable disease/minor response: 16/37 (43%). Patients received a median number of 4 (1–10) treatment cycles. Study treatment was stopped despite a clinical benefit or response in 4/33 patients after reaching maximal epirubicin doses (≤750 mg/m2). VPA peak and trough plasma concentrations increased linearly up to 120 mg/m2. MTD is being defined at 160/100 mg/kg/d VPA. H3 and H4 histone acetylation and topo II expression have been correlated with VPA dose, plasma concentration and response. Conclusion: A sequence-specific combination of VPA and epirubicin is active without exacerbation of epirubicin toxicity. VPA plasma peak and trough levels exceeding concentrations needed for biological effects and in vitro synergy are easily achievable with minimal toxicity. The noteworthy anti-tumor activity seen in this heavily pretreated Phase I population warrants further exploration. [Table: see text]

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A phase I trial of recombinant interleukin-2 combined with recombinant interferon-gamma in patients with cancer.

Journal of Clinical Oncology ◽

10.1200/jco.1990.8.7.1269 ◽

1990 ◽

Vol 8 (7) ◽

pp. 1269-1276 ◽

Cited By ~ 27

Author(s):

B G Redman ◽

L Flaherty ◽

T H Chou ◽

A al-Katib ◽

M Kraut ◽

...

Keyword(s):

Phase I ◽

Interferon Gamma ◽

Phase I Trial ◽

Interleukin 2 ◽

Cell Activity ◽

Ifn Gamma ◽

Recombinant Interferon ◽

Lak Cell ◽

Recombinant Interleukin 2 ◽

Lak Cell Activity

Twenty-six patients with metastatic cancer were entered into a phase I trial of concurrent recombinant interleukin-2 (IL-2) and recombinant interferon-gamma (IFN-gamma). IL-2 was administered as a continuous intravenous infusion for 5 days. IFN-gamma was administered by a daily intramuscular (IM) injection during the 5 days of IL-2 administration. Treatment was repeated twice after 9-day rest periods. After a 2-week rest, patients without evidence of tumor progression were retreated. Natural killer (NK)- and lymphokine-activated killer (LAK)-cell activity were assayed in each patient before treatment, on day 1, and on day 5 of each cycle. Constitutional symptoms occurred in most patients but were not dose-limiting. Other toxicities included hypotension responsive to fluids, transient elevations in liver function tests, erythema/pruritus, eosinophilia, and transient leukopenia/thrombocytopenia. The maximum-tolerated dose (MTD) of the combination was 1 x 10(6) U/m2/d of IL-2 combined with 0.50 mg/m2/d of IFN-gamma. The dose-limiting toxicity was pulmonary manifesting as rales and shortness of breath. The dose of the combination that resulted in the optimal generation of in vivo LAK-cell activity was a dose of at least 0.25 mg/m2/d of IFN-gamma combined with 1 x 10(6) U/m2/d of IL-2. Objective clinical responses were seen in five of 26 patients. These included a partial response of 2 months duration in a patient with non-Hodgkin's lymphoma (NHL), mixed responses in a patient with NHL and two patients with renal cell carcinoma (RCC), and an ongoing assessable response in a patient with bone metastases from RCC. The recommended dose for phase II trials of this combination is 0.50 mg/m2 of IFN-gamma and 1 x 10(6) U of IL-2.

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