Phase I study of a combination of recombinant interferon-alpha and recombinant interferon-gamma in cancer patients.

1986 ◽  
Vol 4 (11) ◽  
pp. 1677-1683 ◽  
Author(s):  
R Kurzrock ◽  
M G Rosenblum ◽  
J R Quesada ◽  
S A Sherwin ◽  
L M Itri ◽  
...  
Keyword(s):  
Interferon Gamma ◽  
Interferon Alpha ◽  
Maximum Tolerated Dose ◽  
Blood Levels ◽  
Recombinant Interferon ◽  
Starting Dose ◽  
The Individual ◽  
Dose Levels ◽  
Recombinant Interferon Alpha

Combinations of interferon-alpha and interferon-gamma demonstrate synergistic antiviral and anti-proliferative activity in vitro. Therefore, we initiated a clinical study of combination interferon therapy in humans. Eighteen patients with metastatic solid tumors received daily intramuscular (IM) injections of recombinant interferon-alpha-A (IFN alfa-2a, Roferon-A; Hoffman-LaRoche, Nutley, NJ) and recombinant IFN-gamma (rIFN-gamma) for 6 weeks. The dose levels were 0.5, 1.0, 2.0, and 5.0 X 10(6) U/m2/d of each interferon. A minimum of two patients were entered sequentially at each dose level. Fever, chills, fatigue, and a greater than or equal to 50% drop in granulocyte counts were observed at all doses. Severity of symptoms corresponded to increasing dose levels. In contrast to the tachyphylaxis to these symptoms that usually develops in patients treated with the individual interferons, many patients on this study experienced persistent fever and worsening fatigue over 6 weeks. The maximum tolerated dose was 1 X 10(6) U/m2/d of each interferon. One patient with renal-cell carcinoma achieved a partial remission (duration, 3 months). Enzyme-linked immunoassay analysis in all four patients for whom complete data were available revealed that peak blood levels of IFN alfa-2a on day 22 were about tenfold higher than on day 1. Because of the possibility of cumulative toxicity, the recommended starting dose for further studies is 0.5 X 10(6) U/m2/d of each interferon, with escalation to 1.0 X 10(6) U/m2/d after 1 month if tolerance is acceptable. Phase II investigations to explore the antitumor efficacy of this regimen are planned.

scholarly journals Opposite effects of recombinant interferon-alpha A and deoxycoformycin on adenosine deaminase activity in the Daudi B lymphoblastoid cell line

Blood ◽  
1988 ◽  
Vol 71 (1) ◽  
pp. 59-64 ◽  
Author(s):  
CR Faltynek
Keyword(s):  
Growth Inhibition ◽  
Cell Line ◽  
Adenosine Deaminase ◽  
Interferon Alpha ◽  
Lymphoblastoid Cell Line ◽  
Recombinant Interferon ◽  
Growth Inhibitory ◽  
Adenosine Deaminase Activity ◽  
Recombinant Interferon Alpha

Abstract Interferon-alpha and the adenosine deaminase (ADA) inhibitor deoxycoformycin (dCF) have each been shown to be efficacious in the treatment of some lymphoid malignancies and to have potent antiproliferative activities in vitro. This study examined whether dCF and recombinant interferon-alpha A (rIFN-alpha A) were additive, synergistic, or antagonistic in their effects on the cultured B lymphoblastoid cell line Daudi. Treatment of Daudi cells for three to four days with doses of rIFN-alpha A that were growth inhibitory was unexpectedly found to increase the level of ADA activity per cell two- to threefold and therefore to prevent the inhibition of ADA by limiting concentrations of dCF. However, the opposite effects of dCF and rIFN- alpha A on ADA activity did not lead to antagonistic effects on growth inhibition. The higher concentrations of dCF (with deoxyadenosine) necessary for appreciable growth inhibition could inhibit the increased ADA activity in rIFN-alpha A-treated cells, thus resulting in additive antiproliferative effects.

In vitro phase II trial of recombinant interferon alpha-2 in gastrointestinal cancer

1985 ◽  
Vol 3 (4) ◽  
pp. 188-198 ◽  
Author(s):  
W. Scheithauer ◽  
E. M. Temsch ◽  
K. Schieder ◽  
H. Funovics ◽  
R. Schiessel ◽  
...  
Keyword(s):  
Interferon Alpha ◽  
Phase Ii ◽  
Gastrointestinal Cancer ◽  
Phase Ii Trial ◽  
Recombinant Interferon ◽  
Recombinant Interferon Alpha

scholarly journals Opposite effects of recombinant interferon-alpha A and deoxycoformycin on adenosine deaminase activity in the Daudi B lymphoblastoid cell line

Blood ◽  
1988 ◽  
Vol 71 (1) ◽  
pp. 59-64
Author(s):  
CR Faltynek
Keyword(s):  
Growth Inhibition ◽  
Cell Line ◽  
Adenosine Deaminase ◽  
Interferon Alpha ◽  
Lymphoblastoid Cell Line ◽  
Recombinant Interferon ◽  
Growth Inhibitory ◽  
Adenosine Deaminase Activity ◽  
Recombinant Interferon Alpha

Interferon-alpha and the adenosine deaminase (ADA) inhibitor deoxycoformycin (dCF) have each been shown to be efficacious in the treatment of some lymphoid malignancies and to have potent antiproliferative activities in vitro. This study examined whether dCF and recombinant interferon-alpha A (rIFN-alpha A) were additive, synergistic, or antagonistic in their effects on the cultured B lymphoblastoid cell line Daudi. Treatment of Daudi cells for three to four days with doses of rIFN-alpha A that were growth inhibitory was unexpectedly found to increase the level of ADA activity per cell two- to threefold and therefore to prevent the inhibition of ADA by limiting concentrations of dCF. However, the opposite effects of dCF and rIFN- alpha A on ADA activity did not lead to antagonistic effects on growth inhibition. The higher concentrations of dCF (with deoxyadenosine) necessary for appreciable growth inhibition could inhibit the increased ADA activity in rIFN-alpha A-treated cells, thus resulting in additive antiproliferative effects.

A phase I study of 2-cyano-3, 12 dioxoolean-1, 9-dien-28-oic acid (CDDO) in advance solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14137-14137 ◽  
Author(s):  
B. Holkova ◽  
S. Kummar ◽  
P. Glauber ◽  
A. Chen ◽  
J. M. Strong ◽  
...  
Keyword(s):  
Dose Level ◽  
Plasma Concentrations ◽  
Maximum Tolerated Dose ◽  
Human Liver Tissue ◽  
Cohort Design ◽  
Starting Dose ◽  
Post Infusion ◽  
Dose Levels ◽  
Dose Limiting Toxicity

14137 Background: CDDO, a synthetic triterpenoid, induces apoptosis through intrinsic and extrinsic pathways, and as a ligand for the transcription factor PPAR-? that controls cellular differentiation and growth inhibition. Methods: CDDO was given as a 5 day continuous infusion every 28 days; starting dose 0.6 mg/m2/hr. Accelerated titration design used, 1 patient (pt)/cohort entered until a single pt has dose-limiting toxicity (DLT) or 2 pts exhibit grade (gr) = 2 toxicity during the first cycle. The study then converts to a standard 3–6 pt/cohort design. Maximum tolerated dose (MTD): Dose at which no more than 1/6 pts have DLT and the dose below which at least 2/6 patients have DLT. Objectives: Determine toxicity profile, pharmacokinetics (PK), and MTD of CDDO. PK were determined by LC-MS/MS analysis of plasma collected pre, during and post CDDO infusion. Results: 6 pts have been accrued thus far up to dose level 6. (19.2 mg/m2). Diagnoses: colon -3, sarcoma-1, bladder -1 and ovary-1. Median age: 52. DLT and MTD have not yet been achieved. Gr 1–2 toxicities have been acceptable: anemia, thrombocytopenia, decreased Na+, Mg++ and albumin, elevated Ca++, transaminases and bilirubin, and anorexia, fatigue and constipation. Gr 4 pulmonary emboli (unrelated to CDDO) was seen in one pt. PK: Steady state CDDO plasma concentrations (Css) in the first 3 dose levels increased linearly (see table ). Post infusion CDDO plasma concentrations decreased in a bi- exponential manner for the first three dose levels. Data indicate that < 1% of CDDO is excreted in the urine unchanged. No oxidative metabolism has been observed; however, we identified a CDDO glucuronide conjugate in urine and in human liver tissue incubations in vitro. Conclusions: The DLT and MTD have not been reached, and accelerated dose escalation continues. Since the CDDO Css appears to increase linearly with dose, we anticipate achieving 1 μM plasma levels at dose level 5 (9.6mg/m2/hr), the effective concentration in preclinical models. [Table: see text] No significant financial relationships to disclose.

Phase II evaluation of recombinant interferon alpha and BCNU in recurrent glioma

1995 ◽  
Vol 82 (3) ◽  
pp. 430-435 ◽  
Author(s):  
Jan C. Buckner ◽  
Loren D. Brown ◽  
John W. Kugler ◽  
Terrence L. Cascino ◽  
James E. Krook ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Antitumor Activity ◽  
Interferon Alpha ◽  
Tumor Regression ◽  
Recurrent Glioma ◽  
Chemotherapy Response ◽  
Recombinant Interferon ◽  
Content Type ◽  
Recombinant Interferon Alpha

✓ The goal of this study was to determine the antitumor activity and toxicity of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) plus recombinant interferon-alpha (IFN-a) in patients with recurrent glioma. As single agents, both BCNU and IFN-α can cause tumor regression in patients with recurrent glioma. In vitro studies suggest synergy between the two agents. Thirty-five patients in whom computerized tomography (CT) or magnetic resonance (MR) evidence was obtained of progressive astrocytoma, oligoastrocytoma, or oligodendroglioma received recombinant IFN-α2a (12 × 106 U/m2 intramuscularly) on Days 1 through 3 and BCNU (150 mg/m2 intravenously) on Day 3 of each 6-week cycle. All patients had tumor progression despite radiation therapy and had received no prior chemotherapy. Response was assessed by CT or MR evidence and by neurological examination while the patients were on a regimen of stable or decreasing doses of corticosteroids. All patients could be evaluated for response and toxicity. Twenty-nine percent of the patients demonstrated objective tumor regression; 37% remained stable for more than 6 months and 25% were stable for less than 6 months. The median duration of response to IFN-α and BCNU was 9.9 months and the median survival for all patients was 13.3 months. Toxicity consisted primarily of moderate myelosuppression, venous irritation, vomiting, flulike symptoms, and transient reversible exacerbation of underlying neurological symptoms. The use of BCNU plus IFN-α is a safe, active regimen in the treatment of patients with recurrent glioma who have failed to respond to prior radiation therapy. The contribution of IFN to the antitumor activity observed in this study compared with that previously described with BCNU alone cannot be assessed from this trial.

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