Therapy of renal cell carcinoma with interleukin-2 and lymphokine-activated killer cells: phase II experience with a hybrid bolus and continuous infusion interleukin-2 regimen.

1990 ◽  
Vol 8 (10) ◽  
pp. 1630-1636 ◽  
Author(s):  
D R Parkinson ◽  
R I Fisher ◽  
A A Rayner ◽  
E Paietta ◽  
K A Margolin ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Continuous Infusion ◽  
Renal Cell ◽  
Response Rate ◽  
Performance Status ◽  
Objective Response ◽  
Interleukin 2 ◽  
High Dose ◽  
Lymphokine Activated Killer Cells

Forty-seven patients with metastatic or unresectable renal cell carcinoma were treated with interleukin-2 (IL-2) and lymphokine-activated killer (LAK)-cell therapy, using a hybrid IL-2 regimen. IL-2 was administered initially by intravenous bolus (10(5) U/kg [Cetus Corp, Emeryville, CA] every 8 hours for 3 days) during the priming phase, and subsequently by continuous infusion (3 x 10(6) U/m2 for 6 days); during this second treatment period, in vitro-generated LAK cells were administered. Despite selection of patients for good performance status (PS) (29, PS 0; 18, PS 1) prior nephrectomy (43 of the 47 patients), and low tumor burden, the response rate was low (two complete [CRs] and two partial responses [PRs], for an overall objective response rate of 9%). Toxicity was comparable to that experienced with the high-dose bolus regimen. These results suggest that the dose and schedule of IL-2 administration may influence the likelihood of response to IL-2 in renal cell carcinoma.

High-dose, continuous infusion Interleukin-2 in the treatment of metastatic renal cell carcinoma: Experience of the C.R.O., Aviano

1996 ◽  
Vol 63 (4) ◽  
pp. 462-466
Author(s):  
R. Sorio ◽  
A. Merlo ◽  
C. Sacco ◽  
S. Morassut ◽  
R. Bortolussi ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Continuous Infusion ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Performance Status ◽  
Interleukin 2 ◽  
High Dose ◽  
Multicentric Study ◽  
The Usa

Interleukin-2 (IL-2, Proleukin, Chiron Therapeutics Inc., Emeryville, CA) has been approved in Italy for the therapy of patients affected by metastatic renal cell carcinoma (RCC) with a good performance status. The basis for approval in the USA and Europe was a series of clinical trials demonstrating that high-dose IL-2, although significantly toxic, can obtain approximately 20% objective responses and improve survival. Between July 1988 and September 1993, 50 patients were treated with high-dose IL-2 in continuous infusion (according to the West protocol), first as part of a European multicentric study, and subsequently as standard treatment. Responses were seen in 9 of the 45 evaluable patients, and, at the last control (December 1995), an improvement in the survival of responding or unchanged patients was clear. This statement may seem excessive but is based on clinical evidence showing a change in the natural history of some of our patients, which is unusual in patients with solid tumors, and in particular RCC patients.

Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy.

1995 ◽  
Vol 13 (3) ◽  
pp. 688-696 ◽  
Author(s):  
G Fyfe ◽  
R I Fisher ◽  
S A Rosenberg ◽  
M Sznol ◽  
D R Parkinson ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Objective Response ◽  
Eastern Cooperative Oncology Group ◽  
Interleukin 2 ◽  
High Dose ◽  
Primary Tumors ◽  
Median Response

PURPOSE To determine the efficacy and toxicity of a high-dose interleukin-2 (IL-2) regimen in patients with metastatic renal cell carcinoma. PATIENTS AND METHODS Two hundred fifty-five assessable patients were entered onto seven phase II clinical trials. Proleukin (aldesleukin; Chiron Corp, Emeryville, CA) 600,000 or 720,000 IU/kg was administered by 15-minute intravenous (i.v.) infusion every 8 hours for up to 14 consecutive doses over 5 days as clinically tolerated with maximum support, including pressors. A second identical cycle of treatment was scheduled following 5 to 9 days of rest, and courses could be repeated every 6 to 12 weeks in stable or responding patients. RESULTS The overall objective response rate was 14% (90% confidence interval [CI], 10% to 19%), with 12 (5%) complete responses (CRs) and 24 (9%) partial responses (PRs). Responses occurred in all sites of disease, including bone, intact primary tumors, and visceral metastases, and in patients with large tumor burdens or bulky individual lesions. The median response duration for patients who achieved a CR has not been reached, but was 19.0 months for those who achieved a PR. Baseline Eastern Cooperative Oncology Group (ECOG) performance status (PS) was the only predictive prognostic factor for response to IL-2. While treatment was associated with severe acute toxicities, these generally reversed rapidly after therapy was completed. However, 4% of patients died of adverse events judged to be possibly or probably treatment-related. CONCLUSION High-dose IL-2 appears to benefit some patients with metastatic renal cell carcinoma by producing durable CRs or PRs. Despite severe acute treatment-associated toxicities, IL-2 should be considered for initial therapy of patients with appropriately selected metastatic renal cell carcinoma.

A randomized phase II trial of continuous infusion interleukin-2 or bolus injection interleukin-2 plus lymphokine-activated killer cells for advanced renal cell carcinoma.

1992 ◽  
Vol 10 (2) ◽  
pp. 275-281 ◽  
Author(s):  
G R Weiss ◽  
K A Margolin ◽  
F R Aronson ◽  
M Sznol ◽  
M B Atkins ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Continuous Infusion ◽  
Renal Cell ◽  
Bolus Injection ◽  
Interleukin 2 ◽  
Lak Cells ◽  
Advanced Renal Cell Carcinoma ◽  
High Dose ◽  
Randomized Phase Ii

PURPOSE Since 1985, multiple centers have demonstrated that interleukin-2 (IL-2) and lymphokine-activated killer (LAK) cells produce durable anticancer responses in patients with metastatic renal cell carcinoma. High-dose recombinant IL-2 (rIL-2) has been administered by intravenous bolus injection (Rosenberg SA, et al: N Engl J Med 313:1485-1492, 1985) and by continuous intravenous infusion (West WH, et al: N Engl J Med 316:898-905, 1987) combined with lymphokine-activated killer (LAK) cells, with both methods producing responses in patients with advanced renal cell carcinoma. The Extramural IL-2/LAK Working Group has conducted a randomized phase II trial of two intravenous high-dose rIL-2 regimens (bolus three times daily or 24-hour continuous infusion) to determine if either one manifests greater anticancer activity or a more acceptable toxicity profile. PATIENTS AND METHODS Ninety-four patients with measurable advanced renal cell carcinoma were enrolled on this study: 46 to the bolus injection arm and 48 to the continuous infusion arm. On both arms, patients underwent a priming phase of rIL-2 administration, four daily lymphocytaphereses to harvest mononuclear cells that were placed in 3- to 4-day culture for generation of LAK cells, and an rIL-2/LAK coadministration phase. Patients were then observed monthly for evidence of response to this therapy and were offered up to two additional courses of treatment every 3 months if evidence of response was detected. RESULTS Twenty percent of patients on the bolus injection arm experienced objective responses (three complete responses and six partial responses); 15% of patients on the continuous infusion arm responded (two complete responses and five partial responses). Complete responses were durable, persisting for 310+ to 700+ days. The incidence of severe life-threatening toxicities typical of high-dose rIL-2 therapy was similar in both arms (eg, patients with hypotension requiring pressors: bolus 71%, continuous 63%; oliguria less than or equal to 200 mL/8 hours: bolus 65%, continuous 71%). More episodes of fever, infection, and serum alkaline phosphatase elevation were associated with the continuous infusion arm, while more thrombocytopenia occurred on the bolus injection arm. Four patients (three bolus injection, one continuous infusion) died of respiratory and circulatory failure while under treatment. No clinical or laboratory parameter accompanying treatment on either arm was, by univariate or multivariate analysis, associated with an increased likelihood of response. CONCLUSIONS Both methods of high-dose rIL-2/LAK cell administration produce nearly equivalent anticancer activity and toxicity in the treatment of renal cell carcinoma. The ability to predict responding patients based on patient or treatment characteristics is not possible.

Phase IB clinical trial of anti-CD3 followed by high-dose bolus interleukin-2 in patients with metastatic melanoma and advanced renal cell carcinoma: clinical and immunologic effects.

1993 ◽  
Vol 11 (8) ◽  
pp. 1496-1505 ◽  
Author(s):  
J A Sosman ◽  
G R Weiss ◽  
K A Margolin ◽  
F R Aronson ◽  
M Sznol ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
T Cells ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Objective Response ◽  
Interleukin 2 ◽  
Maximum Tolerated Dose ◽  
Advanced Melanoma ◽  
High Dose ◽  
Phase Ib

PURPOSE To determine the maximum-tolerated dose (MTD) of an anti-CD3 antibody, OKT3, in combination with high-dose interleukin-2 (IL-2), and to determine whether OKT3 can enhance the expansion of CD3+, CD25+ (IL-2 receptor alpha [IL-2R alpha])-expressing T cells in the peripheral blood of patients with advanced melanoma and renal cell carcinoma receiving high-dose IL-2. PATIENTS AND METHODS We performed a phase IB trial of a murine monoclonal anti-CD3 antibody (OKT3) with high-dose IL-2 in patients with advanced melanoma and renal cell carcinoma. Fifty-four patients were enrolled, with cohorts of 10 or more patients receiving escalating doses of OKT3 at 75, 200, 400, and 600 micrograms/m2 on day 1 followed by IL-2 at an initial dose 0.45 and then 1.33 mg/m2 every 8 hours on days 2 through 6 and 16 through 20 (maximum, 28 doses). An additional cohort of 14 patients received high-dose IL-2 (1.33 mg/m2 per dose) alone. Circulating CD3+, CD25+ cells were monitored before therapy and following the initial week of IL-2. RESULTS A total of 68 patients were enrolled. The MTD for OKT3 was defined as 400 micrograms/m2 based on a reduction in the number of IL-2 doses that could be administered. Increases in CD3+, CD25+ cells were observed within all cohorts; however, the increase was not OKT3 dose-dependent. On the other hand, we found that 60% (nine of 15) of patients tested at OKT3 dose levels of 200, 400, and 600 micrograms/m2 had increases in serum sCD25 (soluble IL-2R alpha) to more than 100,000 U/mL, while none of 10 patients who received IL-2 alone or with OKT3 at the 75-micrograms dose had increases greater than 60,000 U/mL. Of 29 patients with renal cell carcinoma who received OKT3 with IL-2 (1.33 mg/m2), there were three objective tumor responses (all partial responses). In the 16 patients with melanoma who received OKT3 plus IL-2, there was a single objective response (complete response). CONCLUSION The doses of OKT3 administered on this schedule failed to enhance significantly the number of circulating CD3+, CD25+ T cells and did not appear to increase the antitumor activity of IL-2 alone, which underscores the need for other approaches to enhance the efficacy of IL-2 therapy.

A phase II study of S-1 for the treatment of cytokine-refractory metastatic renal cell carcinoma

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5100-5100
Author(s):  
S. Naito ◽  
M. Eto ◽  
N. Shinohara ◽  
Y. Tomita ◽  
M. Fujisawa ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Mrna Expression ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Response Rate ◽  
Performance Status ◽  
Objective Response ◽  
Molar Ratio ◽  
Related Enzyme

5100 Background: S-1 is a novel oral anticancer agent, contains tegafur (FT), a prodrug of 5-fluorouracil (5-FU), with 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate (Oxo) at a molar ratio of FT: CDHP: Oxo = 1:0.4:1. The purpose of this study was to evaluate the efficacy and safety of S-1 in cytokine-refractory metastatic renal cell carcinoma (mRCC), and to examine the relation between response and mRNA expression levels of 5-FU-related enzymes. Methods: Eligible patients had a histologically confirmed diagnosis of clear cell or papillary type of RCC, measurable lesions, treatment histories with cytokines, an ECOG performance status of 0 or 1 (2 was allowed in patients with bone metastasis), an age of at least 20 years, prior nephrectomy, and adequate organ functions. Any prior treatment for mRCC was discontinued more than 4 weeks before registration. S-1 was administered orally at a dose of 40 mg/m2 twice daily for 28 days, followed by 14 days of rest. The primary endpoint was the objective response rate (ORR) as confirmed by an independent reviewer. The planned sample size was 44 patients. The threshold response rate was defined as 5%, and the expected rate was set at 17.5%. If the lower limit of the 95% CI exceeded the threshold rate (6 of the 44), S-1 was evaluated to be effective. Formalin fixed paraffin embedded specimens, which had been obtained by radical nephrectomy, were used for mRNA expression assay, performed by RT-PCR method. Results: Between April 2006 and May 2007, 45 patients were enrolled, and 31 assay samples were obtained. ORR was 24.4% (11/45, 95% CI: 12.9 - 39.5%). The median PFS was 9.2 months. The median OS could not be calculated, but the survival rate at 1 year was 87.5%. The most common grade 3–4 adverse events assessed according to the CTCAE v.3.0 included anemia (6.7%), neutropenia (8.9%), anorexia (8.9%), hyperglycemia (6.7%), stomatitis (4.4%), diarrhea (4.4%), and fatigue (4.4%). On mRNA expression analysis, the expression level of 5-FU-related enzyme correlated with ORR and PFS. Conclusions: S-1 is effective and well tolerated in patients with cytokine-refractory mRCC. Measurement of the mRNA level of 5-FU-related enzyme in tumors before treatment may facilitate prediction of the response to S-1. No significant financial relationships to disclose.

High-dose bolus interleukin-2: Correlating response rate with number of doses received.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 452-452
Author(s):  
Jolly Patel ◽  
Mayer N. Fishman ◽  
Dawn Goetz
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Cumulative Dose ◽  
Stable Disease ◽  
Renal Cell ◽  
Response Rate ◽  
Interleukin 2 ◽  
High Dose ◽  
Significant Difference

452 Background: Administration of high-dose interleukin-2 (IL-2) in metastatic renal cell carcinoma (MRCC) has higher response and survival rates when compared to low dose or subcutaneous administration. In patients who achieve a response, it may be at the expense of more toxicity risk, from more doses. The association of the major response rate with the number of high dose boluses or cumulative dose received is of interest. The primary objective of this study is to evaluate a direct correlation with response and cumulative dose or the total number of doses received. Methods: A retrospective chart review was conducted of all patients at H. Lee Moffitt Cancer Center diagnosed with metastatic renal cell carcinoma who received high dose bolus IL-2 from September 30th, 1999 to September 30th, 2010. The cumulative dose and the number of doses of IL-2 received was recorded and associated with categorical complete response [CR], partial response [PR], stable disease [SD] or progressive disease [PD] response, by treating physician assessment. Sites of metastasis were also documented. The incidence of adverse effects such as renal failure, transaminitis, cardiac arrhythmias, thrombocytopenia as well as rates of infection and ICU transfers were tabulated. Results: 31 out of 55 patients analyzed were assessed at least with stable disease in response to IL-2. Six achieved a CR, 11 achieved a PR, 14 had stable disease and 24 patients had PD as best responses. Among those with CR or PR to IL-2, they received approximately 30 doses of IL-2 (p=0.027 vs. those not in that category). Converesely, those who received a higher cumulative dose were also more likely to respond (p=0.0077). With respect to adverse events, 58% of patients experienced acute renal insufficiency, 63% transaminitis, 40% arrhythmias, and 45% thrombocytopenia. 55% required dopamine use at any point and 11% required use of additional pressors; 15% required an ICU transfer at some point, and approximately 4% developed a documented infection. Conclusions: Cumulative dose or number of high dose bolus doses received is associated with a statistically significant difference in response rate, within the limitations of this retrospective analysis.

Immunomodulation by HDAC inhibition: Results from a phase II study with entinostat and high-dose Interleukin 2 in renal cell carcinoma patients (CTEP#7870).

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 500-500 ◽  
Author(s):  
Roberto Pili ◽  
David I. Quinn ◽  
Hans J. Hammers ◽  
Paul Monk ◽  
Saby George ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Phase I ◽  
Cell Carcinoma ◽  
Phase Ii ◽  
Renal Cell ◽  
Clear Cell ◽  
Objective Response ◽  
Interleukin 2 ◽  
High Dose ◽  
Dose Levels

500 Background: Immunosuppressive factors such as regulatory T cells (Tregs) and myeloid-derived suppressive cells (MDSCs) limit the efficacy of immunotherapies. Histone deacetylase (HDAC) inhibitors have been shown to have immunomodulatory effects. We have previously reported that the class I HDAC inhibitor entinostat has synergistic antitumor effects in combination with high dose interleukin-2 (IL-2) in a renal cell carcinoma model by down-regulating Foxp3 expression and function of Tregs. Thus, we have conducted a Phase I/II clinical study with entinostat and high dose IL-2 in patients (pts) with metastatic clear cell renal cell carcinoma. Methods: The primary objectives were to evaluate the safety, tolerability and efficacy of this combination strategy. The main eligibility criteria were clear cell histology and being fit to receive high dose IL-2. The phase I portion consisted of two dose levels of entinostat (3 and 5 mg, PO every14 days) and a fixed dose of IL-2 (600,000 units/kg every 8 hrs). To test our hypothesis, the fixed sample size at the Phase II dose level was 36 with a type I/II error of 10%. If 11 or more of the pts have a response, the hypothesis that the response rate is ≤ 20% is rejected. Results: Dose levels 1 and 2 were completed without DLTs and 5 mg entinostat was the Phase II recommended dose. No severe adverse events were observed during the first 45 days of treatment. The most common transient grade 3/4 toxicities were lymphopenia (50%), neutropenia (9%), and hypophosphatemia (6%). To date, we have enrolled 39 pts at dose level 2, and 35 have completed one cycle (84 days). Four pts were not evaluable. Twelve pts have achieved objective response (39%; 9 PR, 3 CR) with a median time to response of 81 days (55-96). The median PFS has not been reached with a median follow-up of 437 days (30-1428). Preliminary results show decreased Tregs and monocytic MDSCs following treatment and suggest an association of increased CD14+/CD86+ and CD14+HLADR+cells with objective response. Conclusions: The results from this phase I/II suggest that entinostat may increase the therapeutic effect of high dose IL-2 by modulating immunosuppressive cells (R21CA137649; U01CA70095). Clinical trial information: NCT01038778.

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