United States Intergroup E1609: A phase III randomized study of adjuvant ipilimumab (3 or 10 mg/kg) versus high-dose interferon-α2b for resected high-risk melanoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9504-9504 ◽  
Author(s):  
Ahmad A. Tarhini ◽  
Sandra J. Lee ◽  
F. Stephen Hodi ◽  
Uma N. M. Rao ◽  
Gary Irvin Cohen ◽  
...  
Keyword(s):  
High Risk ◽  
Adjuvant Therapy ◽  
Primary Endpoint ◽  
Randomized Study ◽  
Phase Iii ◽  
High Dose ◽  
High Risk Melanoma ◽  
Relative Safety ◽  
Risk Melanoma ◽  
Systemic Adjuvant Therapy

9504 Background: Phase III adjuvant trials reported significant benefits in relapse-free survival (RFS) for 6 FDA-approved regimens and overall survival (OS) for HDI and ipi10 versus observation or placebo. E1609 evaluated the relative safety and efficacy of ipi at 3 and 10 mg/kg compared to HDI, which was the adjuvant standard until recently. Methods: E1609 had 2 co-primary endpoints: OS and RFS; considered positive if either co-primary endpoint comparison was positive. Activated on 5/25/2011 and completed accrual 8/15/2014. A 2-step hierarchical approach evaluated ipi3 vs HDI followed by ipi10 vs HDI. Patients were stratified by AJCC7 stage (IIIB, IIIC, M1a, M1b). Based on protocol criteria, the primary evaluation was conducted using a data cutoff of 2/15/2019. Results: Final adult patient accrual was 1670; 523 randomized to ipi3, 636 to HDI and 511 to ipi10. Treatment related adverse events (AEs) Grade 3 or higher were experienced by 37% pts with ipi3, 79% with HDI and 58% with ipi10, and those of any grade leading to treatment discontinuation were 35% with ipi3, 20% HDI and 54% ipi10. AEs were mostly immune related and consistent with the known toxicity profiles of these agents. Gr5 AEs considered at least possibly related were 3 with ipi3, 2 with HDI and 8 with ipi10. First step comparison of OS and RFS of ipi3 vs. HDI utilized an ITT analysis of concurrently randomized cases (N = 1051) and showed significant OS difference in favor of ipi3; HR 0.78, 95.6% RCI (.61, 1.00); p = 0.044. The prespecified efficacy boundary was crossed. For RFS, HR 0.85, 99.4% CI (.66, 1.09), p = 0.065. In the 2nd step comparison of ipi10 vs. HDI (N = 989), there were trends towards improvement in OS [HR 0.88, 95.6% CI (.69, 1.12)] and RFS [HR 0.84, 99.4% CI (.65, 1.09)] in favor of ipi10 that were not statistically significant. Conclusions: Adjuvant therapy with ipi3 benefits survival of resected high-risk melanoma pts; for the first time in the history of melanoma adjuvant therapy, E1609 has demonstrated a significant improvement in the primary endpoint of OS against an active control regimen previously shown to have OS and RFS benefits, supporting early systemic adjuvant therapy for high-risk melanoma. Clinical trial information: NCT01274338.

A phase III randomized study of adjuvant ipilimumab (3 or 10 mg/kg) versus high-dose interferon alfa-2b for resected high-risk melanoma (U.S. Intergroup E1609): Preliminary safety and efficacy of the ipilimumab arms.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9500-9500 ◽  
Author(s):  
Ahmad A. Tarhini ◽  
Sandra J. Lee ◽  
F. Stephen Hodi ◽  
Uma N. M. Rao ◽  
Gary I Cohen ◽  
...  
Keyword(s):  
High Risk ◽  
Adjuvant Therapy ◽  
Interferon Alfa ◽  
Regulatory Approval ◽  
High Dose ◽  
Safety And Efficacy ◽  
High Risk Melanoma ◽  
Relative Safety ◽  
Risk Melanoma ◽  
High Dose Interferon

9500 Background: In the U.S., 3 regimens have regulatory approval as adjuvant therapy for high-risk melanoma, including high-dose interferon-alfa (HDI) and ipilimumab 10 mg/kg (ipi10). Ipilimumab 3 mg/kg (ipi3) has regulatory approval for metastatic inoperable melanoma. The toxicity of ipi is dose- dependent, and following the recent approval of adjuvant ipi10, it has become urgent to evaluate the relative safety and efficacy of adjuvant ipi at the 2 dose levels that have been tested in E1609. Methods: E1609 randomized patients (pts) with resected high-risk melanoma (stratified by stages IIIB, IIIC, M1a, M1b) to ipi10 or ipi3 versus HDI. Co-primary endpoints were RFS and OS. The current analysis investigates the relative safety and preliminary, non-comparative RFS of the ipi arms as of 3/2/17. Results: E1609 was activated on 5/25/11 and completed adult pt accrual on 8/15/14. Accrual to ipi10 was suspended due to toxicity between 9/23-11/16/2013. Final adult pt accrual was 1670 including 511 ipi10, 636 HDI and 523 ipi3 pts. Treatment related adverse events (AEs) were reported among 503 ipi10 and 516 ipi3 pts. Worst degree (Gr 3+) AEs were experienced by 57% ipi10 and 36.4% ipi3 pts and were mostly immune related (Table 1). AEs led to discontinuation of treatment in 271 (53.8 %) of 503 ipi10 and in 180 (35.2 %) of 512 ipi3 pts during the initial 4 dose induction phase. Gr5 AEs considered at least possibly related were 8 with ipi10 and 2 with ipi3. At a median follow-up of 3.1 years, an unplanned RFS analysis of ipi3 and ipi10 on concurrently randomized pts showed no difference between the 2 arms. Three-year RFS rate was 54% (95% CI: 49, 60) with ipi10 and 56% (50, 61) with ipi3. Conclusions: Adjuvant therapy of pts with high-risk melanoma is associated with significantly more toxicity at ipi10 compared to ipi3. An unplanned RFS analysis of concurrently randomized pts on the 2 ipi arms showed no difference in RFS. Clinical trial information: NCT01274338. [Table: see text]

High-Dose Interferon Alfa-2b Does Not Diminish Antibody Response to GM2 Vaccination in Patients With Resected Melanoma: Results of the Multicenter Eastern Cooperative Oncology Group Phase II Trial E2696

2001 ◽  
Vol 19 (5) ◽  
pp. 1430-1436 ◽  
Author(s):  
John M. Kirkwood ◽  
Joseph Ibrahim ◽  
David H. Lawson ◽  
Michael B. Atkins ◽  
Sanjiv S. Agarwala ◽  
...  
Keyword(s):  
High Risk ◽  
Phase Ii ◽  
Interferon Alfa ◽  
Immunoglobulin M ◽  
Phase Iii ◽  
High Dose ◽  
High Risk Melanoma ◽  
Risk Melanoma ◽  
High Dose Interferon ◽  
Very High

PURPOSE: High-dose interferon alfa-2b (IFNα2b) is the only established adjuvant therapy of resectable high-risk melanoma. GM2-KLH/QS-21 (GMK) is a chemically defined vaccine that is one of the best developed of a range of vaccine candidates for melanoma. A single-institution phase III trial conducted at Memorial Hospital served as the impetus for an intergroup adjuvant E1694/S9512/C509801 trial, which recently completed enrollment of 880 patients. To build on the apparent benefit of IFNα2b in resectable high-risk American Joint Committee on Cancer (AJCC) stage IIB or III melanoma, this phase II study was designed to evaluate the combination of GMK and IFNα2b. The E2696 trial was undertaken to evaluate the toxicity and other effects of the established adjuvant high-dose IFNα2b regimen in relation to immune responses to GMK and to evaluate the potential clinical and immunologic effects of the combined therapies. PATIENTS AND METHODS: This trial enrolled 107 patients with resectable high- or very high–risk melanoma (AJCC stages IIB, III, and IV). RESULTS: The results demonstrate that IFNα2b does not significantly inhibit immunoglobulin M or G serologic responses to the vaccine and that the combination of high-dose IFNα2b and GMK is well tolerated in this patient population. CONCLUSION: Cox analysis of the results of the combination with IFNα2b show improvement in the relapse-free survival of patients with very high–risk melanoma (including those with resectable M1 disease).

Phase III trial of high-dose interferon alpha-2b versus cisplatin, vinblastine, DTIC plus IL-2 and interferon in patients with high-risk melanoma (SWOG S0008): An intergroup study of CALGB, COG, ECOG, and SWOG.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8504-8504 ◽  
Author(s):  
Lawrence E. Flaherty ◽  
James Moon ◽  
Michael B. Atkins ◽  
Ralph Tuthill ◽  
John A. Thompson ◽  
...  
Keyword(s):  
High Risk ◽  
Stage Iv ◽  
Phase Iii ◽  
Stage Iii ◽  
Rank Test ◽  
High Dose ◽  
Phase Iii Trial ◽  
High Risk Melanoma ◽  
Risk Melanoma ◽  
High Dose Interferon

8504 Background: High-dose interferon for one year (HDI) is the FDA approved adjuvant therapy for patients (pts) with high-risk melanoma (HRM). Efforts to modify IFN dose or schedule have not improved efficacy. A meta-analysis demonstrated that biochemotherapy (BCT) produced superior response rates compared with chemotherapy in pts with stage IV melanoma (Wheatley et al J Clin Oncol 25:5426, 2007). We sought to determine whether a short course of BCT would be more effective than HDI as adjuvant treatment in pts with HRM. Methods: S-0008 (an Intergroup Phase III trial) enrolled pts who were high risk (Stage III A-N2a thru Stage III C N3) and randomized them to receive either HDI or BCT consisting of dacarbazine 800 mg/m2 day 1, cisplatin 20 mg/m2/ days 1-4, vinblastine 1.2 mg/m2 days 1-4, IL-2 9 MIU/m2/day continuous IV days 1-4, IFN 5 MU/m2/day sc days 1-4, 8,10,12, and G-CSF 5 ug/kg/day sc days 7-16. BCT cycles were given every 21 days x 3 cycles (9 weeks total). Pts were stratified for number of involved nodes (1-3 v ≥4), micro v macro metastasis, and ulceration of the primary. Co-primary endpoints were relapse free survival (RFS) and overall survival (OS) using a one-sided log rank test at p= 0.05. Results: 432 pts were enrolled between 8/2000 and 11/2007: 30 were ineligible or withdrew consent. Grade 3 and 4 adverse events occurred in 57% and 7% respectively of HDI pts and 36% and 40% of BCT pts. At a median f/up of 6 yrs, BCT improved RFS (p = 0.02, HR 0.77 [90% CI: 0.62 – 0.96]) with median RFS for BCT of 4.0 yrs (90% CI:1.9 – 5.9) v 1.9 yrs (90% CI: 1.4 – 2.5) and 5 yr RFS of 47% v 39%. Median OS was not different between the two arms (p = 0.49 HR 1.0 [90% CI: 0.78 – 1.27]) with median OS not yet reached for BCT v 8.4 yrs (90% CI: 4.5 – 9.3) for HDI and 5 yr survival 56% for both arms. Conclusions: In HRM pts, BCT provides a statistically significant improvement in RFS compared to HDI, but no discernable difference in OS and more grade IV toxicity. BCT represents a shorter, alternative treatment for pts with HRM, and a potential control arm and basis for future combinations in the adjuvant setting.

Quality-of-Life–Adjusted Survival Analysis of High-Dose Adjuvant Interferon Alfa-2b for High-Risk Melanoma Patients Using Intergroup Clinical Trial Data

2002 ◽  
Vol 20 (5) ◽  
pp. 1311-1318 ◽  
Author(s):  
Kerry L. Kilbridge ◽  
Bernard F. Cole ◽  
John M. Kirkwood ◽  
Frank G. Haluska ◽  
Michael A. Atkins ◽  
...  
Keyword(s):  
Quality Of Life ◽  
High Risk ◽  
Interferon Alfa ◽  
Trial Data ◽  
Phase Iii ◽  
High Dose ◽  
High Risk Melanoma ◽  
Risk Melanoma ◽  
Adjuvant Interferon

PURPOSE: High-dose adjuvant interferon alfa-2b (IFNα2b) for high-risk melanoma is a 1-year regimen that improves relapse-free and overall survival but has significant toxicity. A quality-of-life–adjusted survival (QAS) analysis analysis of two cooperative group phase III trials, E1684 and E1690/S9111/C9190, was performed, incorporating patient values (utilities) for the toxicity of IFNα2b treatment and melanoma recurrence. PATIENTS AND METHODS: Quality-Adjusted Time Without Symptoms or Toxicity methodology was used with melanoma patient utilities and trial data to estimate the effect of IFNα2b on QAS. The increase or decrease in QAS that patients could expect from treatment was estimated based on their utilities. Eleven utility predictor questions were tested to identify patients with utilities that result in decreased QAS. RESULTS: Using E1684 data, IFNα2b would result in an increase in QAS for all sets of patient utilities. This benefit was significant (P < .05) for 16% of patients. Using E1690/S9111/C9190 data, 77% of patients would experience a benefit in QAS from IFNα2b and 23% would experience a decrease in QAS; neither of these effects was statistically significant. Using utility predictors and the E1690/S9111/C9190 analysis, a decision rule was formulated that helps identify patients in whom IFNα2b may detract from QAS. CONCLUSION: Most patients experienced improvement in QAS in both trials, but this benefit was statistically significant in only 16% of patients in E1684. Change in QAS depends more on the utility for IFNα2b toxicity than on the utility for melanoma recurrence. Cancer patients probably have higher utilities for IFNα2b toxicity than members of the general population and will tend to favor IFNα2b treatment as a result.

A phase II randomized study of adjuvant imatinib versus high-dose interferon alpha-2b for resected high-risk c-kit mutated melanoma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e20027-e20027
Author(s):  
Lu Si ◽  
Xuan Wang ◽  
Yan Kong ◽  
Bin Lian ◽  
Zhi Hong Chi ◽  
...  
Keyword(s):  
High Risk ◽  
Adjuvant Therapy ◽  
Randomized Study ◽  
Growth Factor Receptor ◽  
High Dose ◽  
Interferon Alpha 2B ◽  
Risk Melanoma ◽  
Exon 11 ◽  
One Year ◽  
High Dose Interferon

e20027 Background: Imatinib, a selective inhibitor targeting Abl as well as C-Kit and the platelet-derived growth factor receptor, has been tested for the efficacy and toxicities in metastatic melanoma patients harboring mutations in C-Kit gene. High-dose interferon for one year (HDI) is the FDA approved adjuvant therapy for patients (pts) with high-risk melanoma. This study (NCT01782508) aims to see whether imatinib is more effective than interferon alfa-2b in adjuvant therapy for patients with C-Kit mutated melanomas. Methods: This study enrolled C-Kit mutated(exon 9,11 or 13)pts who were high risk (stage IIB to stage IIIC) and randomized them to receive either imatinib (400mg daily for a year) or HDI (interferon a-2b 15X106 U/m2 d1–5/wX4w + 9X106U tiwX48w) in the absence of disease progression or unacceptable toxicity. 40 pts of each group were planned to enroll. Routine tests including blood tests, medical history updates, physical exams and Brain/Chest/Abdomen/Pelvic CT were performed every 2 months. The endpoints were recurrence-free survival (RFS) and overall survival. Results: Through Jan 2013,7 pts were recruited F3 in imatinib arm and 4 in HDI arm. The three pts received imatinib haven’t had recurrence or metastasis. The RFS were 6m+ (Exon 11: W577S), 5m+ (Exon 11: L576P), 5m+ (Exon 11: L576P) respectively. Two pts have already had lung or regional lymphnode at 4 months (Exon 13: K642E) and 5 months (Exon 11: V560D) in the HDI arm. The other two pts (both Exon 11: 579 insert) in the HDI arm were still disease free for 6 months. The toxicities were consistent with the usual reported studies. Conclusions: In the C-Kit mutated melanoma pts, it’s promising that imatinib may provide more beneficial effect than HDI for high-risk melanomas. (Supported by the National Natural Science Foundation of China (30973483, 81172196, 81102068.) Clinical trial information: NCT01782508.

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