Lawrence E. Flaherty

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

PURPOSE The Cytokine Working Group conducted a randomized phase III trial to determine the value of outpatient interleukin-2 (IL-2) and interferon alfa-2b (IFN) relative to high-dose (HD) IL-2 in patients with metastatic renal cell carcinoma. PATIENTS AND METHODS Patients were stratified for bone and liver metastases, primary tumor in place, and Eastern Cooperative Oncology Group performance status 0 or 1 and then randomly assigned to receive either IL-2 (5 MIU/m(2) subcutaneously every 8 hours for three doses on day 1, then daily 5 days/wk for 4 weeks) and IFN (5 MIU/m(2) subcutaneously three times per week for 4 weeks) every 6 weeks or HD IL-2 (600,000 U/kg/dose intravenously every 8 hours on days 1 through 5 and 15 to 19 [maximum 28 doses]) every 12 weeks. RESULTS One hundred ninety-two patients were enrolled between April 1997 and July 2000. Toxicities were as anticipated for these regimens. The response rate was 23.2% (22 of 95 patients) for HD IL-2 versus 9.9% (nine of 91 patients) for IL-2/IFN (P = .018). Ten patients receiving HD IL-2 were progression-free at 3 years versus three patients receiving IL-2 and IFN (P = .082). The median response durations were 24 and 15 [corrected] months (P = .18) [corrected] and median survivals were 17.5 and 13 months (P = .24). For patients with bone or liver metastases (P = .001) or a primary tumor in place (P = .040), survival was superior with HD IL-2. CONCLUSION 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.

Adjuvant immunotherapy of resected, intermediate-thickness, node-negative melanoma with an allogeneic tumor vaccine: Overall results of a randomized trial of the Southwest Oncology Group

PURPOSE Patients with clinically negative nodes constitute over 85% of new melanoma cases. There is no adjuvant therapy for intermediate-thickness, node-negative melanoma patients. PATIENTS AND METHODS The Southwest Oncology Group conducted a randomized phase III trial of an allogeneic melanoma vaccine for 2 years versus observation in patients with intermediate-thickness (1.5 to 4.0 mm or Clarks level IV if thickness unknown), clinically or pathologically node-negative melanoma (T3N0M0). RESULTS Six hundred eighty-nine patients were accrued over 4.5 years; 89 patients (13%) were ineligible. Surgical node staging was performed in 24%, the remainder were clinical N0. Thirteen eligible patients refused assigned treatment: seven on the observation arm and six on the vaccine arm. Most vaccine patients experienced mild to moderate local toxicity, but 26 (9%) experienced grade 3 toxicity. After a median follow-up of 5.6 years, there were 107 events (tumor recurrences or deaths) among the 300 eligible patients randomized to vaccine compared with 114 among the 300 eligible patients randomized to observation (hazard ratio, 0.92; Cox-adjusted P(2) = 0.51). There was no difference in vaccine efficacy among patients with tumors < or = 3 mm or > 3 mm. CONCLUSION This represents one of the largest randomized, controlled trials of adjuvant vaccine therapy in human cancer reported to date. Compliance with randomization was excellent, with only 2% refusing assigned therapy. There is no evidence of improved disease-free survival among patients randomized to receive vaccine, although the power to detect a small but clinically significant difference was low. Future investigations of adjuvant vaccine approaches for patients with intermediate-thickness melanoma should involve larger numbers of patients and ideally should include sentinel node biopsy staging.

Adjuvant Immunotherapy of Resected, Intermediate-Thickness, Node-Negative Melanoma With an Allogeneic Tumor Vaccine: Impact of HLA Class I Antigen Expression on Outcome

PURPOSE An association between expression of > or = two of five HLA class I antigens (HLA-A2, HLA-A28, HLA-B44, HLA-B45, and HLA-C3; collectively called M5) and response to an allogeneic melanoma vaccine (Melacine; Corixa Corporation, Seattle, WA) has been described in stage IV melanoma. This study investigated whether class I antigen expression impacted relapse-free survival (RFS) after adjuvant therapy with this vaccine. PATIENTS AND METHODS We performed class I (HLA-A, HLA-B, and HLA-C) serotyping on patients enrolled onto Southwest Oncology Group Trial 9035, a randomized, observation-controlled, phase III trial of adjuvant Melacine. All patients had clinically node-negative cutaneous melanoma (1.5 to 4.0 mm). Interactions between treatment and class I antigen expression were tested. Analyses involved all serotyped patients and were adjusted for tumor thickness, method of nodal staging, sex, ulceration, and primary tumor site. RESULTS HLA typing was performed on 553 (80%) of the 689 enrolled patients (294 vaccinated and 259 observed). Expression of > or = two M5 antigens was associated with a superior vaccine treatment effect. Among patients who matched > or = two of the M5, the 97 vaccine-treated patients had improved RFS compared with the 78 observation patients (5-year relapse-free survival, 83% v 59%; P =.0002). The major components of this effect were contributed by HLA-A2 and HLA-C3. Among those who were HLA-A2-positive and/or HLA-C3-positive, the 5-year RFS for vaccinated patients was 77%, compared with 64% for observation (P =.004). There was no impact of HLA-A2 and/or HLA-C3 expression among observation patients. CONCLUSION This prospective analysis indicates a highly significant benefit of adjuvant therapy with Melacine among patients expressing > or = two of the M5 class I antigens, validating a prior observation in stage IV disease. HLA-A2 and HLA-C3 contributed most to this effect. Processed melanoma peptides found in Melacine may be presented by HLA-A2 and HLA-C3 and play a role in preventing relapse in vaccinated patients.

Three Phase II Cytokine Working Group Trials of gp100 (210M) Peptide Plus High-Dose Interleukin-2 in Patients With HLA-A2–Positive Advanced Melanoma

PURPOSE High-dose interleukin-2 (IL-2) induces responses in 15% to 20% of patients with advanced melanoma; 5% to 8% are durable complete responses (CRs). The HLA-A2-restricted, modified gp100 peptide (210M) induces T-cell immunity in vivo and has little antitumor activity but, combined with high-dose IL-2, reportedly has a 42% (13 of 31 patients) response rate (RR). We evaluated 210M with one of three different IL-2 schedules to determine whether a basis exists for a phase III trial. PATIENTS AND METHODS In three separate phase II trials, patients with melanoma received 210M subcutaneously during weeks 1, 4, 7, and 10 and standard high-dose IL-2 during weeks 1 and 3 (trial 1), weeks 7 and 9 (trial 2), or weeks 1, 4, 7, and 10 (trial 3). Immune assays were performed on peripheral-blood mononuclear cells collected before and after treatment. RESULTS From 1998 to 2003, 131 patients with HLA-A2-positive were enrolled. With 60-month median follow-up time, the overall RR for 121 assessable patients was 16.5% (95% CI, 10% to 26%); the RRs were 23.8% in trial 1 (42 patients), 12.5% in trial 2 (40 patients), and 12.8% in trial 3 (39 patients). There were 11 CRs (9%) and nine partial responses (7%), with 11 patients (9%) progression free at >or= 30 months. Immune studies including assays of CD3-zeta expression and numbers of CD4(+)/CD25(+)/FoxP3(+) regulatory T cells, CD15(+)/CD11b(+)/CD14(-) immature myeloid-derived cells, and CD8(+)gp100 tetramer-positive cells in the blood did not correlate with clinical benefit. CONCLUSION The results again demonstrate efficacy of high-dose IL-2 in advanced melanoma but did not demonstrate the promising clinical activity reported with vaccine and high-dose IL-2 in any of three phase II trials.

Significant impact of HLA class I allele expression on outcome in melanoma patients treated with an allogeneic melanoma cell lysate vaccine. Final analysis of SWOG-9035

7501 Background: SWOG-9035 compared 2 years of an allogeneic melanoma lysate (Melacine™) to observation in patients (pts) with stage II melanoma 1.5-4.0 mm thick. We also analyzed the effects of expression of certain HLA antigens (≥2 of HLA-A2, A28, B44, B45, C3 - called M5 - or either HLA-A2 and or C3). Now we report the mature overall survival (OS) analysis as planned. METHODS Primary analyses were conducted on the eligible pt population (intent to treat, ITT) using a Cox model adjusted for stratification and recognized prognostic factors. HLA analyses were [Formula: see text], involved all typed pts and were adjusted for stratification and prognostic factors. RESULTS In total, 689 pts were entered over 4.5 years (598 eligible). Median follow-up time is 7.8 years (maximum 10.9 years). Ninety-one patients are ineligible, mostly (n=75) by pathology (tumor too thin or too thick). For the ITT analysis, the 5-year OS for the observation arm is 77% and for the vaccine arm is 81% (p=.98). For all randomized pts, the 5-year OS for the observation arm is 76% and for the vaccine arm is 82% (p=.49). We HLA typed 553 of the total 689 pts enrolled (80% of the total). There was a significant interaction of M5 status (≥2 vs 0-1) and treatment (p=.02). Among pts with 2 or more of the M5, 5-year OS for vaccine pts is 93% and for observation pts is 74% (p=.009). Among patients with 0-1 of the M5, 5-year OS for vaccine pts is 83% and for observation pts is 82% (p=.68). The interaction remained significant when only HLA A2/C3 status was considered (A2+ and/or C3+ vs A2- and C3-, p=.004). In the A2+ and/or C3+ group, 5-year OS for vaccine pts is 90% and for observation pts is 76% (p=.007). In the A2- and C3- group, 5-year OS for vaccine pts is 80% and for observation pts is 84% (p=.16). CONCLUSION There was no significant benefit of vaccine therapy overall, but this prospective analysis indicates significant survival benefit of vaccine therapy among early-stage melanoma pts expressing ≥2 of the M5 alleles. HLA-A2 and C3 were the predominant alleles contributing to this effect. A prospective confirmatory trial in pts expressing HLA-A2 and/or HLA-C3 is planned. No significant financial relationships to disclose.

Inhibition of prostate cancer growth by estramustine and etoposide

Background. Metastatic prostate cancer that is refractory to hormone therapy remains an incurable disease without effective therapy. The authors used the nuclear matrix, the RNA‐protein network of the nucleus that plays an important role in DNA replication and gene expression, as a target for cancer chemotherapy. In pre‐clinical models, estramustine and etoposide appeared to interact to inhibit the growth of the hormone‐refractory prostate cancer cells.