Double-Blind Phase III Randomized Trial of the Antiprogestin Agent Mifepristone in the Treatment of Unresectable Meningioma: SWOG S9005

Purpose Progesterone receptors are expressed in approximately 70% of meningiomas. Mifepristone is an oral antiprogestational agent reported to have modest activity in a phase II study. This multicenter, prospective, randomized, placebo-controlled phase III trial conducted by SWOG was planned to define the role of mifepristone in the treatment of unresectable meningioma. Patients and Methods Eligible patients were randomly assigned to receive either mifepristone or placebo for 2 years unless disease progressed. Patients who were stable or responding to protocol therapy after 2 years had the option to continue with the same blinded therapy. Serial follow-up allowed assessment of efficacy and toxicity. Time to treatment failure and overall survival were ascertained for all randomly assigned patients. On progression, patients receiving placebo could cross over and receive active drug. Results Among 164 eligible patients, 80 were randomly assigned to mifepristone and 84 to placebo. Twenty-four patients (30%) were able to complete 2 years of mifepristone without disease progression, adverse effects, or other reasons for discontinuation. Twenty-eight patients (33%) in the placebo arm completed the 2-year study. There was no statistical difference between the arms in terms of failure-free or overall survival. Conclusion Long-term administration of mifepristone was well tolerated but had no impact on patients with unresectable meningioma.

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Prolonged Overall Survival with Lenalidomide Plus Dexamethasone Compared with Dexamethasone Alone in Patients with Relapsed or Refractory Multiple Myeloma.

Blood ◽

10.1182/blood.v110.11.412.412 ◽

2007 ◽

Vol 110 (11) ◽

pp. 412-412 ◽

Cited By ~ 14

Author(s):

Donna Weber ◽

Robert Knight ◽

Christine Chen ◽

Andrew Spencer ◽

Zhinuan Yu ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Prior Treatment ◽

Phase Iii ◽

P Value ◽

Double Blind ◽

Prior Therapy ◽

Phase Iii Trials

Abstract Introduction: Lenalidomide (Len), an analog of thalidomide (Thal) is a novel, oral, immunomodulatory agent that is effective against multiple myeloma (MM). In 2 prospective, randomized, double-blind, placebo-controlled phase III trials, Len with dexamethasone (Dex) induced a significantly higher overall response (OR) rate and complete remission (CR) rate, as well as longer time-to-progression (TTP) in comparison with Dex alone. Here, we investigate the long-term overall survival (OS) with Len/Dex. Methods: We evaluated the pooled results from both randomized trials (MM-009, MM-010) of 704 patients who had relapsed or refractory MM, without prior resistance to Dex, who received either Len (25 mg daily for 3 weeks every 4 weeks), or placebo. Dex was given at 40 mg on days 1–4, 9–12, 17–20 every 4 weeks for 4 cycles. From cycle 5 onwards, Dex was given at 40 mg on days 1–4 only. Response rate and TTP are based on data obtained before unblinding (June 2005 [MM-009] and August 2005 [MM-010]). Follow-up data on OS were obtained up to January 2007. Forty-seven percent of patients who received placebo/Dex crossed over to receive Len +/− Dex. Results: Of 704 patients, 353 were treated with Len/Dex and 351 with Dex alone. Baseline characteristics were well balanced between patients receiving Len/Dex and those receiving Dex alone. Median TTP, OR, and CR were significantly improved in patients treated with Len/Dex compared with Dex alone (Table). Of patients who progressed on Dex alone prior to unblinding, or were found to be receiving Dex alone after unblinding, 47% crossed over to Len +/− Dex. Despite these patients crossing over to Len +/− Dex at progression or at the time of unblinding, the OS was significantly improved in patients treated with Len/Dex compared with Dex alone (hazard ratio 1.295; 95% confidence interval 1.040–1.614; p=0.02). Median OS in the Len/Dex group was 35 months and 31 in the Dex alone group (p<0.05). Median OS was also significantly longer with Len/Dex compared with Dex alone in patients with more than 1 prior therapy (32.4 months versus 27.3 months, p<0.05). Similar median OS was observed with Len/Dex and Dex alone in patients with 1 prior therapy (median OS not yet reached and 35.3 months, p=0.24). Conclusion: With increased follow-up and despite cross-over, patients treated first with Len/Dex had significantly improved OS compared with those treated with Dex alone. Len/Dex (n=353) Dex alone (n=351) P value OR, % 60.6 21.9 <0.001 CR, % 15.0 2.0 <0.001 Median TTP, months 11.2 4.7 <0.001 Median OS, months 35.0 31.0 <0.05 Median OS in patients with 1 prior treatment, months not yet reached 35.3 0.24 Median OS in patients with >1 prior treatment, months 32.4 27.3 <0.05

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Results of a Randomized, Double-Blind, Placebo-Controlled, Phase III Trial of Trifluridine/Tipiracil (TAS-102) Monotherapy in Asian Patients With Previously Treated Metastatic Colorectal Cancer: The TERRA Study

Journal of Clinical Oncology ◽

10.1200/jco.2017.74.3245 ◽

2018 ◽

Vol 36 (4) ◽

pp. 350-358 ◽

Cited By ~ 54

Author(s):

Jianming Xu ◽

Tae Won Kim ◽

Lin Shen ◽

Virote Sriuranpong ◽

Hongming Pan ◽

...

Keyword(s):

Colorectal Cancer ◽

Overall Survival ◽

Metastatic Colorectal Cancer ◽

Biologic Therapy ◽

Phase Iii ◽

Double Blind ◽

Phase Iii Trial ◽

Double Blind Placebo ◽

Asian Patients ◽

To Receive

Purpose Trifluridine/tipiracil (TAS-102) was effective in patients with metastatic colorectal cancer (mCRC) in a phase II Japanese trial. This regional trial evaluated the efficacy and safety of trifluridine/tipiracil in Asian patients with mCRC with or without exposure to biologic therapy. Patients and Methods This randomized, double-blind, placebo-controlled, phase III trial was conducted at 30 sites in China, the Republic of Korea, and Thailand. Patients ≥ 18 years old with histologically or cytologically confirmed adenocarcinoma of the colon or rectum and known KRAS status who were refractory or intolerant to two or more prior chemotherapy regimens were enrolled. Eligible patients were randomly assigned (2:1 ratio; minimization method) to receive trifluridine/tipiracil (twice per day orally; 5 days on and 2 days off for 2 weeks, followed by 14 days off per cycle) or placebo. The primary end point was overall survival (intent-to-treat population). Results Between October 16, 2013, and June 15, 2015, 406 patients were randomly assigned to receive trifluridine/tipiracil (n = 271) or placebo (n = 135). Risk of death was significantly lower in the trifluridine/tipiracil arm than in the placebo arm (hazard ratio for death, 0.79; 95% CI, 0.62 to 0.99; log-rank P = .035). Median overall survival was significantly longer in the trifluridine/tipiracil than in the placebo arm (7.8 months [95% CI, 7.1 to 8.8 months] v 7.1 months [95% CI, 5.9 to 8.2 months], respectively), for a median survival follow-up time of 13.8 months (95% CI, 13.1 to 15.3 months) compared with 13.4 months (95% CI, 11.6 to 17.3 months), respectively. The incidence of serious adverse events was similar between the arms (trifluridine/tipiracil, n = 63 [23.2%]; placebo, n = 32 [23.7%]). No treatment-related deaths were reported. Conclusion Trifluridine/tipiracil has a statistically significant survival benefit compared with placebo in Asian patients with mCRC refractory or intolerant to standard chemotherapies, regardless of exposure to biologic therapy. The safety profile is similar to previous reports.

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Consolidation with Alemtuzumab Improves Progression-Free Survival in Patients with Chronic Lymphocytic Leukemia (CLL) in First Remission - Long-Term Follow-Up of a Randomized Phase III Trial of the German CLL Study Group (GCLLSG).

Blood ◽

10.1182/blood.v108.11.33.33 ◽

2006 ◽

Vol 108 (11) ◽

pp. 33-33 ◽

Cited By ~ 12

Author(s):

C. Schweighofer ◽

M. Ritgen ◽

B. Eichhorst ◽

R. Busch ◽

M. Kneba ◽

...

Keyword(s):

Progression Free Survival ◽

Phase Iii ◽

Consolidation Therapy ◽

First Line ◽

Phase Iii Trial ◽

Free Survival ◽

To Receive ◽

Line Chemotherapy

Abstract Purpose: Alemtuzumab (MabCampath) is a humanized monoclonal antibody that targets the CD52 antigen, which is highly expressed on most human B and T lymphocytes. Alemtuzumab has shown considerable activity in both relapsed/refractory CLL and in the frontline treatment setting. In a recent study, treatment with single-agent alemtuzumab induced MRD-negative remissions in 20% of patients with relapsed/refractory CLL (Moreton et al JCO 2005;23:2971–2979). Other studies suggest that MRD negativity can also be attained when alemtuzumab is administered as consolidation for patients with CLL who achieve incomplete initial responses to chemotherapy. Here, we report our long-term experience within a randomized phase III trial that investigates the role of alemtuzumab for consolidation therapy in patients with previously untreated CLL. Methods: Pts in complete or partial remission after induction chemotherapy, with either fludarabine (F) or fludarabine plus cyclophosphamide (FC), were randomized to receive either alemtuzumab 30 mg, 3 times a week for ≤12 wks or no further treatment. Of 21 eligible pts, who had responded to induction with F or FC (1 CR, 1 nPR, 9 PRs), 11 pts (median age: 60 years) randomized to receive alemtuzumab consolidation and 10 to the observation arm. Pts in the alemtuzumab arm received standard premedication and infection prophylaxis with famciclovir and trimethoprim/sulfamethoxazole. Results: After a median follow-up of 48 months, calculated from time of randomization within this consolidation trial, progression-free survival (PFS) was significantly improved for pts who received alemtuzumab consolidation compared to those who received no further treatment (median PFS not reached versus 20.6 months, P = 0.004). PFS from the beginning of induction therapy with F or FC is also significantly greater for patients in the alemtuzumab consolidation arm versus the observation arm. So far, 3 of 11 pts presented with disease progression after alemtuzumab consolidation compared with 8/10 progressing pts in the observation arm. Differences in PFS between both arms were not associated with disease stage before first line treatment, type of first line chemotherapy (F vs. FC) or response status before initiation of consolidation therapy (CR vs. nPR vs. PR). Correlations between achievement of MRD negative responses and PFS is still under investigation and is planned for presentation. With the exception of 2 patients (1 pt in each arm) all patients remain alive. The study was stopped prematurely due to severe infections (7 CTC III infections, which included 4 CMV reactivations, 1 CTC IV infection) in 7/11 patients being treated with alemtuzumab. However, these infections were successfully treated, not associated with the cumulative dose of alemtuzumab, and no late complications of consolidation therapy have been observed. Conclusions: Although based on few pts due to incomplete accrual, long-term PFS was significantly prolonged in patients with CLL receiving alemtuzumab consolidation after first line chemotherapy with F or FC. An ongoing phase I/II trial of the GCLLSG (CLL2i) is currently evaluating the optimal dose and schedule of alemtuzumab in CLL pts after fludarabine-based chemotherapy.

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Overall survival at 5 years of follow-up in a phase III trial comparing ipilimumab 10 mg/kg with 3 mg/kg in patients with advanced melanoma

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2019-000391 ◽

2020 ◽

Vol 8 (1) ◽

pp. e000391

Author(s):

Paolo Antonio Ascierto ◽

Michelle Del Vecchio ◽

Andrzej Mackiewicz ◽

Caroline Robert ◽

Vanna Chiarion-Sileni ◽

...

Keyword(s):

Overall Survival ◽

Advanced Melanoma ◽

Phase Iii ◽

Double Blind ◽

Term Survival ◽

Phase Iii Trial ◽

Unresectable Stage ◽

Registration Number ◽

Grade 3

BackgroundWe have previously reported significantly longer overall survival (OS) with ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with advanced melanoma, with higher incidences of adverse events (AEs) at 10 mg/kg. This follow-up analysis reports a 5-year update of OS and safety.MethodsThis randomized, multicenter, double-blind, phase III trial included patients with untreated or previously treated unresectable stage III or IV melanoma. Patients were randomly assigned (1:1) to ipilimumab 10 mg/kg or 3 mg/kg every 3 weeks for 4 doses. The primary end point was OS.ResultsAt a minimum follow-up of 61 months, median OS was 15.7 months (95% CI 11.6 to 17.8) at 10 mg/kg and 11.5 months (95% CI 9.9 to 13.3) at 3 mg/kg (HR 0.84, 95% CI 0.71 to 0.99; p=0.04). In a subgroup analysis, median OS of patients with asymptomatic brain metastasis was 7.0 months (95% CI 4.0 to 12.8) in the 10 mg/kg group and 5.7 months (95% CI 4.2 to 7.0) in the 3 mg/kg group. In patients with wild-type or mutantBRAFtumors, median OS was 13.8 months (95% CI 10.2 to 17.0) and 33.2 months (95% CI 19.4 to 45.2) in the 10 mg/kg group, and 11.2 months (95% CI 9.2 to 13.8) and 19.7 months (95% CI 11.6 to 25.3) in the 3 mg/kg group, respectively. The incidence of grade 3/4 treatment-related AEs was 36% in the 10 mg/kg group vs 20% in the 3 mg/kg group, and deaths due to treatment-related AEs occurred in four (1%) and two patients (1%), respectively.ConclusionsThis 61-month follow-up of a phase III trial showed sustained long-term survival in patients with advanced melanoma who started metastatic treatment with ipilimumab monotherapy, and confirmed the significant benefit for those who received ipilimumab 10 mg/kg vs 3 mg/kg. These results suggest the emergence of a plateau in the OS curve, consistent with previous ipilimumab studies.Trial registration numberNCT01515189.

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Update of AMC 0101 study: A phase III trial of intraperitoneal cisplatin and early mitomycin-C plus long-term doxifluridine plus cisplatin (iceMFP) versus mitomycin-C plus short-term doxifluridine (Mf) as adjuvant chemotherapy for grossly serosa-positive advanced gastric cancer (NCT00296322).

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.4_suppl.4 ◽

2012 ◽

Vol 30 (4_suppl) ◽

pp. 4-4 ◽

Cited By ~ 4

Author(s):

Yoon-Koo Kang ◽

Baek-Yeol Ryoo ◽

Heung-Moon Chang ◽

Dae Young Zang ◽

Tae Won Kim ◽

...

Keyword(s):

Adjuvant Chemotherapy ◽

Mitomycin C ◽

Stage I ◽

Phase Iii ◽

Phase Iii Trial ◽

Early Start ◽

Intent To Treat ◽

To Receive

4 Background: To improve the adjuvant chemotherapy in serosa-involving AGC, we adopted intraperitoneal and early start of chemotherapy, as well as prolongation of fluoropyrimidine and addition of cisplatin (P) to Mf regimen. The primary efficacy results of AMC0101 study on 3y relapse free survival rate (RFSR) were presented in 2008 ASCO. Now, we update the results with longer follow up. Methods: Pts with serosa-positive AGC who underwent curative resection were randomized to receive either Mf or iceMFP. Pts with postoperative stage I or IV (M1) were excluded. For Mf, 20 mg/m2 of mitomycin-C (M) was injected 3-6 wks after surgery and 4 wks later, 460-600 mg/m2/day of doxifluridine was administered orally for 3 months. For iceMFP, 100 mg of P was administered intraperitoneally for 2 h during surgery and 15 mg/m2 of M was injected 1 day after surgery. Doxifluridine was started 4 wks after surgery and extended for a total of 12 months and 6 shots of monthly 60 mg/m2 of P were added. Results: Between Oct 2001 and Apr 2007, 640 pts were randomized (318 in Mf, 322 in iceMFP). One hundred and nineteen pts (60 in Mf, 59 in iceMFP) were excluded (postoperative stage I in 90, M1 in 13, positive resection margin in 10, and others in 6). Therefore, a total of 521 pts (258 in Mf, 263 in iceMFP) were eligible for intent-to-treat analysis. Postoperative stages were II in 33.4%, IIIA in 31.9%, IIIB in 17.5%, and IV in 17.3% of pts. As of April 2011, with a median follow-up of 6.6 years, iceMFP group had a significantly longer RFS (HR, 0.73; 95% C.I. 0.57 - 0.93; p=0.0092) and overall survival (HR, 0.77; 95% C.I. 0.60 - 0.98; p=0.0365) than Mf group. Conclusions: We could confirm with longer follow up that benefit in 3y RFSR from iceMFP could be translated into benefit in 5y OSR. Considering no benefit of adding cisplatin and prolongation of doxifluridine to Mf chemotherapy in curatively resected AGC pts (AMC 0201), intraperitoneal cisplatin and/or early start of chemotherapy seemed to be responsible for the improved efficacy of iceMFP chemotherapy in this study.

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Update on overall survival in COLUMBUS: A randomized phase III trial of encorafenib (ENCO) plus binimetinib (BINI) versus vemurafenib (VEM) or ENCO in patients with BRAF V600-mutant melanoma.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.10012 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 10012-10012 ◽

Cited By ~ 3

Author(s):

Helen Gogas ◽

Paolo Antonio Ascierto ◽

Keith Flaherty ◽

Ana Arance ◽

Mario Mandalà ◽

...

Keyword(s):

Overall Survival ◽

Objective Response ◽

Progression Free Survival ◽

Mek Inhibitor ◽

Phase Iii ◽

Phase Iii Trial ◽

Risk Of Death ◽

Term Tolerability

10012 Background: Treatment of patients with BRAF V600–mutant melanoma includes BRAF/MEK-inhibitor combinations based on demonstrated benefits on progression-free survival (PFS) and overall survival (OS). To better understand the proportion of patients who derive long-lived benefit and their characteristics, we performed an updated analysis of OS and other endpoints from the COLUMBUS trial. Methods: In Part 1 of COLUMBUS, 577 patients with advanced/metastatic BRAF V600‒mutant melanoma, untreated or progressed after first-line immunotherapy, were randomized 1:1:1 to ENCO 450 mg QD + BINI 45 mg BID (COMBO450) vs VEM 960 mg BID (VEM) or ENCO 300 mg QD (ENCO300). An updated analysis including PFS, OS, objective response rate (ORR), and safety was conducted after an additional 24 months’ follow-up from the initial analysis. The study is ongoing. Results: At data cutoff (November 2019, as-is data), events had occurred in 65%, 59%, and 75% of patients in the COMBO450, ENCO300, and VEM treatment arms, respectively. Across arms, median follow-up for OS was 60.6 months (mo), with median OS of 33.6 mo (95% CI, 24.4–39.2) for COMBO450, 23.5 mo (95% CI, 19.6–33.6) for ENCO300, and 16.9 mo (95% CI, 14.0–24.5) for VEM. Compared to VEM, COMBO450 decreased the risk of death by 38% (HR, 0.62 [95% CI, 0.49–0.79]). Updated median PFS was COMBO450, 14.9 mo (95% CI, 11.0–20.2), ENCO300, 9.6 mo (95% CI, 7.4–14.8), and VEM, 7.3 mo (95% CI, 5.6–7.9). PFS was longer for COMBO450 vs VEM (HR, 0.52 [95% CI, 0.40–0.67]). A landmark analysis showed a higher rate of OS for COMBO450 at each year analyzed, with OS rates at 4 years of 39%, 37%, and 26% COMBO450, ENCO300, and VEM, respectively. Updated safety analysis confirmed the beneficial long-term tolerability of COMBO450. Conclusions: In the COLUMBUS trial, results for updated PFS and OS with COMBO450 continue to demonstrate long-term benefits in patients with BRAF V600‒mutated melanoma. Clinical trial information: NCT01909453.

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Long-Term Follow-Up of the E1199 Phase III Trial Evaluating the Role of Taxane and Schedule in Operable Breast Cancer

Breast Diseases A Year Book Quarterly ◽

10.1016/j.breastdis.2016.07.003 ◽

2016 ◽

Vol 27 (3) ◽

pp. 218-220

Author(s):

L.H. Prochaska ◽

P. Sharma

Keyword(s):

Breast Cancer ◽

Operable Breast Cancer ◽

Phase Iii ◽

Phase Iii Trial ◽

Long Term Follow Up

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Efficacy of Melphalan and Prednisone Plus Thalidomide in Patients Older Than 75 Years With Newly Diagnosed Multiple Myeloma: IFM 01/01 Trial

Journal of Clinical Oncology ◽

10.1200/jco.2008.21.0948 ◽

2009 ◽

Vol 27 (22) ◽

pp. 3664-3670 ◽

Cited By ~ 284

Author(s):

Cyrille Hulin ◽

Thierry Facon ◽

Philippe Rodon ◽

Brigitte Pegourie ◽

Lotfi Benboubker ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Elderly Patients ◽

Progression Free Survival ◽

Phase Iii ◽

Standards Of Care ◽

Newly Diagnosed ◽

Grade 3 ◽

To Receive

Purpose Until recently, melphalan and prednisone were the standards of care in elderly patients with multiple myeloma. The addition of thalidomide to this combination demonstrated a survival benefit for patients age 65 to 75 years. This randomized, placebo-controlled, phase III trial investigated the efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed myeloma. Patients and Methods Between April 2002 and December 2006, 232 previously untreated patients with myeloma, age 75 years or older, were enrolled and 229 were randomly assigned to treatment. All patients received melphalan (0.2 mg/kg/d) plus prednisone (2 mg/kg/d) for 12 courses (day 1 to 4) every 6 weeks. Patients were randomly assigned to receive 100 mg/d of oral thalidomide (n = 113) or placebo (n = 116), continuously for 72 weeks. The primary end point was overall survival. Results After a median follow-up of 47.5 months, overall survival was significantly longer in patients who received melphalan and prednisone plus thalidomide compared with those who received melphalan and prednisone plus placebo (median, 44.0 v 29.1 months; P = .028). Progression-free survival was significantly prolonged in the melphalan and prednisone plus thalidomide group (median, 24.1 v 18.5 months; P = .001). Two adverse events were significantly increased in the melphalan and prednisone plus thalidomide group: grade 2 to 4 peripheral neuropathy (20% v 5% in the melphalan and prednisone plus placebo group; P < .001) and grade 3 to 4 neutropenia (23% v 9%; P = .003). Conclusion This trial confirms the superiority of the combination melphalan and prednisone plus thalidomide over melphalan and prednisone alone for prolonging survival in very elderly patients with newly diagnosed myeloma. Toxicity was acceptable.

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