Randomized Phase III Trial of High-Dose Interleukin-2 Versus Subcutaneous Interleukin-2 and Interferon in Patients With Metastatic Renal Cell Carcinoma

McDermott, David F.; Regan, Meredith M.; Clark, Joseph I.; Flaherty, Lawrence E.; Weiss, Geoffrey R.; Logan, Theodore F.; Kirkwood, John M.; Gordon, Michael; Sosman, Jeffrey A.; Ernstoff, Marc S.; Tretter, Christopher P.G.; Urba, Walter J.; Smith, John W.; Margolin, Kim; Mier, James W.; Gollob, Jared; Dutcher, Janice P.; Atkins, Michael B.

doi:10.1200/jco.2005.03.206

Cited by 730 publications

(390 citation statements)

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“…Several studies have been published in the past 10 years looking at the efficacy of interferon (MRCRC Collaborators, 1999;Pyrhonen et al, 1999), IL-2 (Yang et al, 2003b;McDermott et al, 2005;Tannir et al, 2006), and antivascular-targeted therapies (Hainsworth et al, 2005;Escudier et al, 2007;Motzer et al, 2007) in the treatment of patients with metastatic RCC. These treatments demonstrate incremental gains in survival (MRCRC Collaborators, 1999;Pyrhonen et al, 1999), a small but consistent and durable complete response rate (Yang et al, 2003b;McDermott et al, 2005) or prolonged progression-free survival rates (Hainsworth et al, 2005;Escudier et al, 2007;Motzer et al, 2007).…”

Section: Vaccination Of Metastatic Rcc Patients E Jonasch Et Almentioning

confidence: 99%

“…These treatments demonstrate incremental gains in survival (MRCRC Collaborators, 1999;Pyrhonen et al, 1999), a small but consistent and durable complete response rate (Yang et al, 2003b;McDermott et al, 2005) or prolonged progression-free survival rates (Hainsworth et al, 2005;Escudier et al, 2007;Motzer et al, 2007). From a clinical perspective, vitespen does not reach the threshold of therapy when compared to these other agents.…”

Section: Vaccination Of Metastatic Rcc Patients E Jonasch Et Almentioning

confidence: 99%

“…Evidence that clear-cell RCC is an immunogenic tumour includes observed spontaneous tumour regression in 1 -4% of patients (Elhilali et al, 2000), the presence of lymphocytic infiltrates in tumour, and responsiveness of RCC to cytokine therapy. A number of studies have been reported demonstrating the ability of interferon alpha and interleukin-2 (IL-2) to engender a tumour response (Fyfe et al, 1995;Pyrhonen et al, 1999;MRCRC Collaborators, 1999;Yang et al, 2003b;McDermott et al, 2005). High-dose IL-2 has consistently resulted in complete responses in 4 -8% of patients, with durable responses in the majority of these individuals (Fyfe et al, 1995;Yang et al, 2003a;McDermott et al, 2005).…”

mentioning

confidence: 99%

“…A number of studies have been reported demonstrating the ability of interferon alpha and interleukin-2 (IL-2) to engender a tumour response (Fyfe et al, 1995;Pyrhonen et al, 1999;MRCRC Collaborators, 1999;Yang et al, 2003b;McDermott et al, 2005). High-dose IL-2 has consistently resulted in complete responses in 4 -8% of patients, with durable responses in the majority of these individuals (Fyfe et al, 1995;Yang et al, 2003a;McDermott et al, 2005). In the case of interferon, two randomised studies demonstrated a modest survival advantage for those who received the agent (MRCRC Collaborators, 1999;Pyrhonen et al, 1999).…”

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confidence: 99%

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Vaccination of metastatic renal cell carcinoma patients with autologous tumour-derived vitespen vaccine: clinical findings

et al. 2008

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The aim of this study was to evaluate the clinical efficacy as determined by time to progression and response rate (RR) of autologous vitespen (formerly HSPPC-96; Oncophage, Antigenics Inc., New York, NY, USA) with and without interleukin-2 (IL-2; Proleukin: Chiron, Emoryville, CA, USA) in stage IV metastatic renal cell carcinoma (RCC) patients undergoing nephrectomy. Eighty-four patients were enrolled on study, and then underwent nephrectomy and harvest of tumour tissue for use in autologous vaccine manufacture. Initial treatment schedule started approximately 4 weeks after surgery and consisted of six injections: once weekly for 4 weeks, then two injections biweekly (vaccines administered at weeks 1, 2, 3, 4, 6, 8), followed by restaging at or around week 10. Patients who had stable or responsive disease continued to receive vaccine, with four more vaccinations biweekly (at weeks 10, 12, 14, 16). Patients who had progressive disease at week-10 evaluation received four consecutive 5-day-per-week courses of 11 × 10 6 U of IL-2 subcutaneously (weeks 10, 11, 12, 13), with four doses of vitespen at 2-week intervals (at weeks 10, 12, 14, 16). At the next evaluation (week 18), patients with a complete response received two further cycles of vitespen (with IL-2 if also received during prior cycle) or until vaccine supply was exhausted. Patients with stable disease or partial response repeated their prior cycle of therapy. Disease progressors who had not yet received IL-2 began IL-2 treatment, and progressors who had already received IL-2 came off study. Of 60 evaluable patients, 2 demonstrated complete response (CR), 2 showed partial response (PR), 7 showed stable disease, and 33 patients progressed. Sixteen patients had unconfirmed stable disease. Two patients who progressed on vaccine alone experienced disease stabilisation when IL-2 was added. Treatment with vitespen did not result in a discernable benefit in the majority of patients with metastatic RCC treated in this study. Use in combination with immunoregulatory agents may enhance the efficacy of vitespen.

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Section: Vaccination Of Metastatic Rcc Patients E Jonasch Et Almentioning

confidence: 99%

Section: Vaccination Of Metastatic Rcc Patients E Jonasch Et Almentioning

confidence: 99%

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Vaccination of metastatic renal cell carcinoma patients with autologous tumour-derived vitespen vaccine: clinical findings

et al. 2008

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“…The other patient died due to thrombocytopenia/bowel infarction and this death was possibly related to treatment. Randomised trials of IL-2 and histamine in MRCC F Donskov et al treatment alone in terms of long-term survival (Negrier et al, 1998;McDermott et al, 2005). Histamine dihydrochloride as an adjunct to IL-2 is an example of translational research from basic biology to clinical trials.…”

Section: Toxicitymentioning

confidence: 99%

Two randomised phase II trials of subcutaneous interleukin-2 and histamine dihydrochloride in patients with metastatic renal cell carcinoma

et al. 2005

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Histamine inhibits formation and release of phagocyte-derived reactive oxygen species, and thereby protects natural killer and T cells against oxidative damage. Thus, the addition of histamine may potentially improve the efficacy of interleukin-2 (IL-2). Two randomised phase II trials of IL-2 with or without histamine dihydrochloride (HDC) in patients with metastatic renal cell carcinoma (mRCC) were run in parallel. A total of 41 patients were included in Manchester, UK and 63 in Aarhus, Denmark. The selfadministered, outpatient regimen included IL-2 as a fixed dose, 18 MIU s.c. once daily, 5 days per week for 3 weeks followed by 2 weeks rest. Histamine dihydrochloride was added twice daily, 1.0 mg s.c., concomitantly with IL-2. A maximum of four cycles were given. The Danish study showed a statistically significant 1-year survival benefit (76 vs 47%, P ¼ 0.03), a trend towards benefit in both median survival (18.3 vs 11.4 months, P ¼ 0.07), time to PD (4.5 vs 2.2 months, P ¼ 0.13) and clinical benefit (CR þ PR þ SD) (58 vs 37%, P ¼ 0.10) in favour of IL-2/HDC, whereas the UK study was negative for all end points. Only three patients had grade 4 toxicity; however, two were fatal. A randomised phase III trial is warranted to clarify the potential role of adding histamine to IL-2 in mRCC.

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Immunotherapy for advanced renal cell cancer

Coppin

Porzsolt

Autenrieth

et al. 2004

Cochrane Database of Systematic Reviews

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Randomized Phase III Trial of High-Dose Interleukin-2 Versus Subcutaneous Interleukin-2 and Interferon in Patients With Metastatic Renal Cell Carcinoma

Abstract: This randomized phase III trial provides additional evidence that HD IL-2 should remain the preferred therapy for selected patients with metastatic renal cell carcinoma.

Cited by 730 publications

References 18 publications

Vaccination of metastatic renal cell carcinoma patients with autologous tumour-derived vitespen vaccine: clinical findings

Vaccination of metastatic renal cell carcinoma patients with autologous tumour-derived vitespen vaccine: clinical findings

Two randomised phase II trials of subcutaneous interleukin-2 and histamine dihydrochloride in patients with metastatic renal cell carcinoma

Immunotherapy for advanced renal cell cancer

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