Large Randomized Study of Thymosin α 1, Interferon Alfa, or Both in Combination With Dacarbazine in Patients With Metastatic Melanoma

PurposeThymosin α 1 (Tα1) is an immunomodulatory polypeptide that enhances effector T-cell responses. In this large randomized study, we evaluated the efficacy and safety of combining Tα1 with dacarbazine (DTIC) and interferon alfa (IFN-α) in patients with metastatic melanoma.Patients and MethodsFour hundred eighty-eight patients were randomly assigned to five treatment groups: DTIC+IFN-α+Tα1 (1.6 mg); DTIC+IFN-α+Tα1 (3.2 mg); DTIC+IFN-α+Tα1 (6.4 mg); DTIC+Tα1 (3.2 mg); DTIC+IFN-α (control group). The primary end point was best overall response at study end (12 months). Secondary end points included duration of response, overall survival (OS), and progression-free survival (PFS). Patients were observed for up to 24 months.ResultsTen and 12 tumor responses were observed in the DTIC+IFN-α+Tα1 (3.2 mg) and DTIC+Tα1 (3.2 mg) groups, respectively, versus four in the control group, which was sufficient to reject the null hypothesis that P0≤ .05 (expected response rate of standard therapy) in these two arms. Duration of response ranged from 1.9 to 23.2 months in patients given Tα1 and from 4.4 to 8.4 months in the control group. Median OS was 9.4 months in patients given Tα1 versus 6.6 months in the control group (hazard ratio = 0.80; 9% CI, 0.63 to 1.02; P = .08). An increase in PFS was observed in patients given Tα1 versus the control group (hazard ratio = 0.80; 95% CI, 0.63 to 1.01; P = .06). Addition of Tα1 to DTIC and IFN-α did not lead to any additional toxicity.ConclusionThese results suggest Tα1 has activity in patients with metastatic melanoma and provide rationale for further clinical evaluation of this agent.

Download Full-text

A phase III multi-institutional randomized study of immunization with the gp100: 209–217(210M) peptide followed by high-dose IL-2 compared with high-dose IL-2 alone in patients with metastatic melanoma

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.18_suppl.cra9011 ◽

2009 ◽

Vol 27 (18_suppl) ◽

pp. CRA9011-CRA9011 ◽

Cited By ~ 33

Author(s):

D. J. Schwartzentruber ◽

D. Lawson ◽

J. Richards ◽

R. M. Conry ◽

D. Miller ◽

...

Keyword(s):

Metastatic Melanoma ◽

Nature Medicine ◽

Randomized Study ◽

Locally Advanced ◽

Peptide Vaccine ◽

Progression Free Survival ◽

Hla Typing ◽

Phase Iii ◽

High Dose ◽

Free Survival

CRA9011 Background: In a phase II study, 13 (42%) of 31 patients with metastatic melanoma receiving high-dose (HD) IL-2 plus gp100:209–217(210M) peptide experienced objective responses (S.A. Rosenberg, et al, Nature Medicine 4: 321–327, 1998). Other studies showed a lower response rate (RR) but no randomized studies have been done. Methods: A prospective randomized phase III trial was conducted at 21 centers with 185 patients. Eligibility: stage IV or locally advanced stage III cutaneous melanoma, HLA A0201, no brain metastases, eligible for HD IL-2, and no previous HD IL-2 or gp100:209–217(210M). Arm 1 received HD IL-2 alone (720,000 IU/kg/dose) and Arm 2 gp100:209–217(210M) peptide + Montanide ISA followed by HD IL-2. The primary objective was clinical response. Secondary objectives were toxicity, disease free/progression free survival, immunologic response and quality of life. Central HLA typing, pathology review, and blinded response assessment were done at the NIH. Central data monitoring was done by The EMMES Corp. and a Data Safety Monitoring Board. Results: Numbers of patients enrolled, treated, and evaluable for response in Arm 1 were 94, 93, and 93 respectively; in Arm 2 91, 86, and 86. Toxicities were consistent with HD IL-2 ± vaccine. Investigator assessed RR showed significant improvement in overall RR for Arm 2=22.1% vs 9.7% (P=0.0223, Chi-Square) and progression free survival (PFS) in favor of Arm 2=2.9 months (1.7–4.5) vs 1.6 (1.5–1.8) (P=0.0101). Median overall survival favors Arm 2=17.6 months (11.8–26.6) vs 12.8 (8.7–16.3) (P=0.0964). Blinded response review is ongoing. Conclusions: RR and PFS were superior with peptide vaccine and HD IL-2 compared to HD IL-2 alone. This represents the first evidence of clinical benefit of vaccination in patients with melanoma. [Table: see text]

Download Full-text

Interferon alfa-2a and interleukin-2 with or without cisplatin in metastatic melanoma: a randomized trial of the European Organization for Research and Treatment of Cancer Melanoma Cooperative Group.

Journal of Clinical Oncology ◽

10.1200/jco.1997.15.7.2579 ◽

1997 ◽

Vol 15 (7) ◽

pp. 2579-2588 ◽

Cited By ~ 150

Author(s):

U Keilholz ◽

S H Goey ◽

C J Punt ◽

T M Proebstle ◽

R Salzmann ◽

...

Keyword(s):

Metastatic Melanoma ◽

Response Rate ◽

Interleukin 2 ◽

Progression Free Survival ◽

Interferon Alfa ◽

Survival Duration ◽

High Dose ◽

Free Survival ◽

Ifn Alpha ◽

Cytokine Treatment

PURPOSE The combination of interferon alfa-2a (IFN alpha) and high-dose interleukin-2 (IL-2) is active in metastatic melanoma. The addition of cisplatin (CDDP) has resulted in response rates greater than 50%. This study was performed to determine whether the addition of CDDP to a cytokine treatment regimen with IFN alpha and high-dose IL-2 influences survival of patients with metastatic melanoma. PATIENTS AND METHODS Patients with advanced metastatic melanoma were randomly assigned to receive treatment with IFN alpha 10 x 10(6) U/m2 subcutaneously on days 1 through 5 and a high-dose intravenous decrescendo regimen of IL-2 on days 3 through 8 (18 mIU/ m2/6 hours, 18 mIU/m2/12 hours, 18 mIU/m2/24 hours, and 4.5 mIU/m2/24 hours x 3) without (arm A) or with (arm B) CDDP 100 mg/m2 on day 1. Treatment cycles were repeated every 28 days to a maximum of four cycles. RESULTS One hundred thirty-eight patients with advanced metastatic melanoma, of whom 87% had visceral metastases, were accrued for the trial. Both regimens were feasible in a multicenter setting. The objective response rate was 18% without and 33% with CDDP (P = .04). The progression-free survival was 53 days without and 92 days with CDDP (P = .02, Wilcoxon; P = .09, log-rank). There was no statistically significant difference in survival between treatment arms, with a median overall survival duration for all patients of 9 months. CONCLUSION The addition of CDDP to cytokine treatment with IFN alpha and IL-2 does not influence survival of patients with advanced metastatic melanoma, despite a significant increase in response rate and progression-free survival.

Download Full-text

Phase III Trial Comparing Concurrent Biochemotherapy With Cisplatin, Vinblastine, Dacarbazine, Interleukin-2, and Interferon Alfa-2b With Cisplatin, Vinblastine, and Dacarbazine Alone in Patients With Metastatic Malignant Melanoma (E3695): A Trial Coordinated by the Eastern Cooperative Oncology Group

Journal of Clinical Oncology ◽

10.1200/jco.2008.17.5448 ◽

2008 ◽

Vol 26 (35) ◽

pp. 5748-5754 ◽

Cited By ~ 208

Author(s):

Michael B. Atkins ◽

Jessie Hsu ◽

Sandra Lee ◽

Gary I. Cohen ◽

Lawrence E. Flaherty ◽

...

Keyword(s):

Overall Survival ◽

Metastatic Melanoma ◽

Interleukin 2 ◽

Progression Free Survival ◽

Response Rates ◽

Interferon Alfa ◽

Phase Iii ◽

Phase Iii Trial ◽

Free Survival ◽

Median Progression Free Survival

Purpose Phase II trials with biochemotherapy (BCT) have shown encouraging response rates in metastatic melanoma, and meta-analyses and one phase III trial have suggested a survival benefit. In an effort to determine the relative efficacy of BCT compared with chemotherapy alone, a phase III trial was performed within the United States Intergroup. Patients and Methods Patients were randomly assigned to receive cisplatin, vinblastine, and dacarbazine (CVD) either alone or concurrent with interleukin-2 and interferon alfa-2b (BCT). Treatment cycles were repeated at 21-day intervals for a maximum of four cycles. Tumor response was assessed after cycles 2 and 4, then every 3 months. Results Four hundred fifteen patients were enrolled, and 395 patients (CVD, n = 195; BCT, n = 200) were deemed eligible and assessable. The two study arms were well balanced for stratification factors and other prognostic factors. Response rate was 19.5% for BCT and 13.8% for CVD (P = .140). Median progression-free survival was significantly longer for BCT than for CVD (4.8 v 2.9 months; P = .015), although this did not translate into an advantage in either median overall survival (9.0 v 8.7 months) or the percentage of patients alive at 1 year (41% v 36.9%). More patients experienced grade 3 or worse toxic events with BCT than CVD (95% v 73%; P = .001). Conclusion Although BCT produced slightly higher response rates and longer median progression-free survival than CVD alone, this was not associated with either improved overall survival or durable responses. Considering the extra toxicity and complexity, this concurrent BCT regimen cannot be recommended for patients with metastatic melanoma.

Download Full-text

Efficacy and safety of endostar in the treatment of advanced lung squamous cell carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e20574 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e20574-e20574

Author(s):

Weiheng Hu ◽

Jian Fang ◽

Jun Nie ◽

Ling Dai ◽

Jie Zhang ◽

...

Keyword(s):

Group Versus ◽

Lung Squamous Cell Carcinoma ◽

Progression Free Survival ◽

Control Group ◽

Efficacy And Safety ◽

Free Survival ◽

Treatment Groups ◽

The Difference ◽

Nsclc Patients

e20574 Background: From the early 2000s, many advances in non-small cell lung cancer (NSCLC) have been made with the emergence of targeted therapies. However, because of safety concerns and a lower prevalence of relevant therapeutic targets, patients with squamous NSCLC have been excluded from many of these breakthroughs. Endostar is a novel inhibitor of tumor angiogenesis that acts specifically on neovascular endothelial cells. This study is to explore the clinical efficacy and safety of endostar in advanced squamous NSCLC patients. Methods: We performed a retrospective analysis of 259 newly diagnosed advanced squamous NSCLC patients who had received platinum-based doublet chemotherapy (PBDC) between September 2009 and March 2016. Of these patients, 116 received Endostar combined with PBDC, and 143 received PBDC only. Clinical tumor responses, progression-free survival (PFS), overall survival (OS), and toxicity profiles were recorded and analyzed. Results: After a median follow-up of 13.5 months, a improvement in PFS was observed in the Endostar group, the median PFS was7.7 months compared with 5.4 months in the control group (HR, 0.745; P= 0.034). The median OS was 19.0 months in the Endostar group versus 14.3 months in the control group, but the difference was not significant (HR, 0.780; P= 0.094). Multivariate analysis demonstrated that in patients with advanced squamous NSCLC, anti-angiogenesis therapy with Endostar, radiotherapy of primary tumor and Ⅲb stage were significant and independent predictors of improved PFS ( P< 0.05). For both arms, hematologic and gastrointestinal toxicities were the most common adverse events. Patients treated with Endostar had slightly higher rates of cardiac disorder and thromboembolic event, as compared with the control patients, but there were no statistically significant differences in toxicities overall between the 2 treatment groups. Conclusions: The current study indicates that Endostar as an anti-angiogenesis therapy combined with PBDC is able to provide further survival benefits with satisfactory toxicity in previously untreated squamous NSCLC patients, which merits further evaluation in randomized trials.

Download Full-text

Outcomes in Clinically Relevant Patient Subgroups From the EMBRACA Study: Talazoparib vs Physician’s Choice Standard-of-Care Chemotherapy

JNCI Cancer Spectrum ◽

10.1093/jncics/pkz085 ◽

2019 ◽

Vol 4 (1) ◽

Cited By ~ 1

Author(s):

Hope S Rugo ◽

Johannes Ettl ◽

Sara A Hurvitz ◽

Anthony Gonçalves ◽

Kyung-Hun Lee ◽

...

Keyword(s):

Breast Cancer ◽

Confidence Interval ◽

Clinical Benefit ◽

Odds Ratio ◽

Objective Response ◽

Progression Free Survival ◽

Hazard Ratio ◽

Free Survival ◽

Duration Of Response ◽

Patient Subgroups

Abstract Background Talazoparib is a poly(adenosine diphosphate-ribose) polymerase inhibitor that causes death in cells with breast cancer susceptibility gene 1 or 2 (BRCA1/2) mutations. Methods EMBRACA (NCT01945775) was a randomized phase III study comparing efficacy, safety, and patient-reported outcomes (PROs) of talazoparib (1 mg) with physician’s choice of chemotherapy (PCT: capecitabine, eribulin, gemcitabine, vinorelbine) in locally advanced or metastatic breast cancer with a germline BRCA1/2 (gBRCA1/2) mutation. Prespecified patient subgroups were analyzed for progression-free survival, objective response, clinical benefit, duration of response, and safety. PROs were evaluated in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) or triple-negative breast cancer (TNBC) subgroups. Results Of 431 patients, 287 were randomly assigned to talazoparib and 144 to PCT. Prespecified subgroup analyses showed prolonged progression-free survival with talazoparib (HR+/HER2−: hazard ratio = 0.47, 95% confidence interval = 0.32 to 0.71; TNBC: hazard ratio = 0.60, 95% confidence interval = 0.41 to 0.87) and greater objective response rate (odds ratio = 1.97 to 11.89), clinical benefit rate (odds ratio = 2.05 to 7.77), and duration of response with talazoparib in all subgroups. PROs in HR+/HER2− and TNBC subgroups showed consistent overall improvement and delay in time to definitive clinically meaningful deterioration with talazoparib vs PCT. Across subgroups, common adverse events included anemia, fatigue, and nausea with talazoparib and neutropenia, fatigue, and nausea with PCT. Seven patients (2.4%) receiving talazoparib had grade II alopecia and 22.7% had grade I alopecia. Conclusions Across all patient subgroups with gBRCA-mutated advanced breast cancer, talazoparib demonstrated clinically significant superiority in outcomes compared with PCT.

Download Full-text

Immediate and long-term results of the first line chemotherapy in patients with metastatic triple negative breast cancer. Final analysis of randomized study

HEALTH OF WOMAN ◽

10.15574/hw.2020.149.75 ◽

2020 ◽

pp. 75-80

Author(s):

S.A. Lyalkin ◽

◽

L.A. Syvak ◽

N.O. Verevkina ◽

◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Randomized Study ◽

Progression Free Survival ◽

First Line ◽

Free Survival ◽

Group 2 ◽

Line Chemotherapy ◽

Group 1

The objective: was to evaluate the efficacy of the first line chemotherapy in patients with metastatic triple negative breast cancer (TNBC). Materials and methods. Open randomized study was performed including 122 patients with metastatic TNBC. The efficacy and safety of the first line chemotherapy of regimens АТ (n=59) – group 1, patients received doxorubicine 60 мг/м2 and paclitaxel 175 мг/м2 and ТР (n=63) – group 2, patients received paclitaxel 175 мг/м2 and carboplatin AUC 5 were evaluated. Results. The median duration of response was 9.5 months (4.5–13.25 months) in patients received AT regimen and 8.5 months (4.7–12.25 months), in TP regimen; no statistically significant differences were observed, р=0.836. The median progression free survival was 7 months (95% CI 5–26 months) in group 1 and 7.5 months (95% CI 6–35 months) in group 2, p=0.85. Both chemotherapy regimens (AT and TP) had mild or moderate toxicity profiles (grade 1 or 2 in most patients). No significant difference in gastrointestinal toxicity was observed. The incidence of grade 3–4 neutropenia was higher in patients of group 2 (TP regimen): 42.8% versus 27% (р<0.05). Conclusions. Both regimens of chemotherapy (AT and TP) are appropriate to use in the first line setting in patients with metastatic TNBC. Key words: metastatic triple negative breast cancer, chemotherapy, progression free survival, chemotherapy toxicity.

Download Full-text

No Impact of NRAS Mutation on Features of Primary and Metastatic Melanoma or on Outcomes of Checkpoint Inhibitor Immunotherapy: An Italian Melanoma Intergroup (IMI) Study

Cancers ◽

10.3390/cancers13030475 ◽

2021 ◽

Vol 13 (3) ◽

pp. 475

Author(s):

Michele Guida ◽

Nicola Bartolomeo ◽

Pietro Quaglino ◽

Gabriele Madonna ◽

Jacopo Pigozzo ◽

...

Keyword(s):

Metastatic Melanoma ◽

Checkpoint Inhibitor ◽

Progression Free Survival ◽

Nras Mutation ◽

Disease Free Interval ◽

Free Survival ◽

Mutational Status ◽

Metastatic Sites ◽

Disease Free ◽

Mutant Braf

Aims: It is debated whether the NRAS-mutant melanoma is more aggressive than NRAS wildtype. It is equally controversial whether NRAS-mutant metastatic melanoma (MM) is more responsive to checkpoint inhibitor immunotherapy (CII). 331 patients treated with CII as first-line were retrospectively recruited: 162 NRAS-mutant/BRAF wild-type (mut/wt) and 169 wt/wt. We compared the two cohorts regarding the characteristics of primary and metastatic disease, disease-free interval (DFI) and outcome to CII. No substantial differences were observed between the two groups at melanoma onset, except for a more frequent ulceration in the wt/wt group (p = 0.03). Also, the DFI was very similar in the two cohorts. In advanced disease, we only found lung and brain progression more frequent in the wt/wt group. Regarding the outcomes to CII, no significant differences were reported in overall response rate (ORR), disease control rate (DCR), progression free survival (PFS) or overall survival (OS) (42% versus 37%, 60% versus 59%, 12 (95% CI, 7–18) versus 9 months (95% CI, 6–16) and 32 (95% CI, 23–49) versus 27 months (95% CI, 16–35), respectively). Irrespectively of mutational status, a longer OS was significantly associated with normal LDH, <3 metastatic sites, lower white blood cell and platelet count, lower neutrophil-to-lymphocyte (N/L) ratio. Our data do not show increased aggressiveness and higher responsiveness to CII in NRAS-mutant MM.

Download Full-text

Long-term progression-free survival of patients with metastatic melanoma or renal cell carcinoma following high-dose interleukin-2

Journal of Investigative Medicine ◽

10.1136/jim-2020-001650 ◽

2021 ◽

Vol 69 (4) ◽

pp. 888-892

Author(s):

Joseph I Clark ◽

Brendan Curti ◽

Elizabeth J Davis ◽

Howard Kaufman ◽

Asim Amin ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Metastatic Melanoma ◽

Systemic Therapy ◽

Renal Cell ◽

Interleukin 2 ◽

Progression Free Survival ◽

High Dose ◽

Free Survival

High-dose interleukin-2 (HD IL-2) was approved in the 1990s after demonstrating durable complete responses (CRs) in some patients with metastatic melanoma (mM) and metastatic renal cell carcinoma (mRCC). Patients who achieve this level of disease control have also demonstrated improved survival compared with patients who progress, but limited data are available describing the long-term course. The aim of this study was to better characterize long-term survival following successful HD IL-2 treatment in patients with no subsequent systemic therapy. Eleven HD IL-2 treatment centers identified patients with survival ≥5 years after HD IL-2, with no subsequent systemic therapy. Survival was evaluated from the date of IL-2 treatment to June 2017. Treatment courses consisted of 2 1-week cycles of HD IL-2. Patients were treated with HD IL-2 alone, or HD IL-2 followed by local therapy to achieve maximal response. 100 patients are reported: 54 patients with mM and 46 patients with mRCC. Progression-free survival (PFS) after HD IL-2 ranges from 5+ years to 30+ years, with a median follow-up of 10+ years. 27 mRCC and 32 mM are alive ≥10 years after IL-2. Thus, a small subset of patients with mM and mRCC achieve long-term PFS (≥5 years) after treatment with HD IL-2 as their only systemic therapy. The ability of HD IL-2 therapy to induce prolonged PFS should be a major consideration in studies of new immunotherapy combinations for mM and mRCC.

Download Full-text

A prospective randomized study to assess the efficacy of post-operative nasal medication after endonasal surgery

The Journal of Laryngology & Otology ◽

10.1017/s0022215100130865 ◽

1995 ◽

Vol 109 (7) ◽

pp. 618-621 ◽

Cited By ~ 3

Author(s):

Paul D. R. Spraggs ◽

Marcelle Macnamara ◽

Theo Joseph

Keyword(s):

Randomized Study ◽

Correlation Coefficients ◽

Control Group ◽

Time Intervals ◽

Treatment Groups ◽

Ephedrine Hydrochloride ◽

Patent Airway ◽

Significant Difference ◽

Blood Clots ◽

Betamethasone Sodium Phosphate

AbstractPost-operative nasal medications are commonly used following routine septal or turbinate surgery but their efficacy in removing blood clots, improving the sensation of a patent airway and promoting healing are unknown. This prospective randomized trial of patients undergoing septal and/or turbinate surgery assessed the efficacy of three commonly used nasal medicines, 0.5 per cent ephedrine hydrochloride nasal drops, betamethasone sodium phosphate (Betnosol®) nose drops and alkaline nasal douches, in producing the sensation of a patent airway in the 14 days following surgery. Ninety-seven patients were randomized into the three treatment groups and a control group who received no nasal medication. Patients assessed their nasal patency by means of a visual analogue scale (VAS) and any complications of treatment were recorded. Statistical analysis of the 76 complete sets of results using the Mann-Whitney U-test showed that there was a significant difference in the distribution of all of the treatments for each of the time intervals (p<0.05). Glass rank biserial correlation coefficients were all small (rg<0.085) but the most significant differences were between ephedrine and the control group at two hours, two, seven and 10 days (0.02, 0.054, 0.057, 0.085 respectively), alkaline nasal douches being most significant at four and 14 days (0.06 and 0.0722 respectively).

Download Full-text