Phase II, Randomized, Controlled, Double-Blinded Trial of Weekly Elesclomol Plus Paclitaxel Versus Paclitaxel Alone for Stage IV Metastatic Melanoma

2009 ◽  
Vol 27 (32) ◽  
pp. 5452-5458 ◽  
Author(s):  
Steven O'Day ◽  
Rene Gonzalez ◽  
David Lawson ◽  
Robert Weber ◽  
Laura Hutchins ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Disease Progression ◽  
Evaluation Criteria ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Phase Iii Trial ◽  
Free Survival ◽  
Double Blinded ◽  
Post Hoc

Purpose Elesclomol is a novel, small-molecule, oxidative stress inducer believed to exert selective cytotoxicity by increasing intracellular concentrations of reactive oxygen species, which results in cell death via mitochondrial apoptosis. We evaluated whether the addition of elesclomol to weekly paclitaxel could improve efficacy in patients with stage IV metastatic melanoma. Patients and Methods We randomly assigned patients with metastatic melanoma, measurable disease, and one or fewer prior chemotherapy regimens to elesclomol 213 mg/m2 plus paclitaxel 80 mg/m2 (E + P) or to paclitaxel 80 mg/m2 alone at a 2:1 ratio; regimens were given as a 1-hour intravenous infusion weekly, during 3 of every 4 weeks until disease progression per Response Evaluation Criteria in Solid Tumors or death occurred. Patients who experienced progression were unblended, and patients on paclitaxel alone were permitted to cross over to E + P. The primary efficacy end point was progression-free survival (PFS); secondary end points were response rate (RR), toxicity, and overall survival (OS; analyzed post hoc). Results At 21 US sites, 53 patients were randomly assigned to E + P, and 28 patients were randomly assigned to paclitaxel. The addition of elesclomol to paclitaxel yielded a doubling of median PFS (112 v 56 days) and a 41.7% risk reduction for disease progression/death (hazard ratio, 0.583; P = .035). Respective RRs for the E + P and paclitaxel groups were 15% and 3%; median OS was 11.9 v 7.8 months. Of patients on paclitaxel alone, 19 (68%) of 28 crossed over to E + P after they experienced progression. Weekly E + P was well tolerated. Conclusion E + P resulted in a statistically significant doubling of median PFS, with an acceptable toxicity profile and encouraging OS. A multinational, phase III trial (SYMMETRY) of E + P compared with paclitaxel alone in metastatic melanoma has closed.

A phase III trial of nab-paclitaxel versus dacarbazine in chemotherapy-naive patients with metastatic melanoma: A subanalysis based on BRAF status.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 9030-9030 ◽  
Author(s):  
Evan Hersh ◽  
Michele Del Vecchio ◽  
Michael Paul Brown ◽  
Richard Kefford ◽  
Carmen Loquai ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Braf Mutation ◽  
Performance Status ◽  
Braf Inhibitor ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Ecog Performance Status ◽  
Mutation Status ◽  
Phase Iii Trial

9030 Background: Activating mutations of BRAF V600 can be found in 40%-50% of melanomas and are related to poor prognosis. In a phase 3 trial for the treatment of metastatic melanoma (MM) in chemotherapy-naive patients, nab-paclitaxel (nab-P) vs dacarbazine (DTIC) demonstrated a significant improvement in the primary endpoint of progression-free survival (PFS), assessed by independent radiological review (IRR), and a trend toward prolonged overall survival (OS) at the interim survival analysis. The study also explored the effect of BRAF status on the efficacy parameters. Methods: Chemotherapy-naive patients with stage IV melanoma (M1c stage 65%; elevated LDH 28%) and ECOG performance status 0-1 were randomized to nab-P 150 mg/m2 on days 1, 8, and 15 of a 28-day cycle (n = 264) or DTIC 1000 mg/m2 on day 1 of each 21-day cycle (n = 265) independent of BRAF status. Prespecified subgroup analyses of final PFS and interim OS in subgroups by BRAF status (V600E mutant, wild-type, or unknown) were performed. Results: BRAF mutation status was balanced between the treatment arms, with 36% and 38% of patients with known BRAF mutation status in the nab-P and DTIC arms, respectively. Patient characteristics were also balanced within BRAF subgroups. As shown in the Table, advantage in the nab-P arm vs DTIC arm was observed for both PFS and interim OS regardless of BRAFmutation status. Poststudy BRAF inhibitor treatment was also balanced. Conclusions: In this phase III trial, treatment effect was independent of BRAF mutation status, benefiting all patients who received nab-P vs DTIC. Therefore nab-P should be considered in the armamentarium for all chemotherapy-naive patients with MM. Clinical trial information: NCT00864253. [Table: see text]

scholarly journals 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

2008 ◽  
Vol 26 (35) ◽  
pp. 5748-5754 ◽  
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.

Five years' results of the German ARO 04-01 trial of concurrent 72 Gy hyperfractionated accelerated radiation therapy (HART) plus once weekly cisplatinum/5-FU versus mitomycin C/5-FU in stage IV head and neck cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 5512-5512 ◽  
Author(s):  
Volker Budach ◽  
Chie-Hee Cho ◽  
Benedikt Sedlmaier ◽  
Michael Wittlinger ◽  
Heinrich Iro ◽  
...  
Keyword(s):  
Stage Iv ◽  
Progression Free Survival ◽  
Repeated Measurements ◽  
Phase Iii ◽  
Phase Iii Trial ◽  
Free Survival ◽  
Regional Control ◽  
Late Morbidity ◽  
Radiation Sequelae

5512 Background: Are 6 cycles of once weekly DDP plus one cycle of 5-FU with concurrent HART superior to 2 cycles of MMC plus one cycle of 5-FU in terms of overall survival (OS) and metastases-free survival (MFS)? Methods: Eligibility: Stage IV SCC of oro(OP)- and hypopharynx(HP), KFS of ≥80% stratified for sites, N-status, grading, hemoglobin and center. The HART schedule was reported elsewhere (V.Budach, JCO 23;2005). HART was applied concurrently with DDP/5-FU at 30mg/m² days 1,8,15,22,29,36 or MMC/5-FU at 10mg/m2 day 1+36 and for both arms with 600mg/m² 5-FU days 1-5 as 120 hrs. c.i. TVD dose prescription was 72 Gy using 3D-conformal or IMRT-TP. 364 patients were analysed using an ITT principle for OS, MFS, progression-free survival (PFS) and loco-regional control (LRC). Hazard ratio (HR) calculations were adjusted for competing risk factors. Results: Median follow-up was 48 mos. for both arms. Mean age was 55.4 years, 83/17% were male/female and 100% stage IV patients (UICC 2002). 58.5%/41.5% of all patients suffered from OP- or HP cancer, respectively. The OS and MFS at 4 years for the DDP- versus MMC-arm was 42.1% vs. 38.8% (n.s.) and 67.3% vs. 56.6% (p=.05), respectively. The LRC and PFS for the DDP versus MMC-arm was 58.6% vs. 57.2% (n.s.) and 46.4% vs. 38.7% (n.s.). Seven items recorded for acute toxicity and 9 for late morbidity showed no significant differences between the treatment arms except for creatinine for the DDP-arm (p < 0.001) using nonparametric analyses of variances for repeated measurements. The overall compliance rates for RTX were 96%, DDP: 72%, 5-FU: 97%, MMC: 86%, respectively. Conclusions: This phase III trial first establishes level IB-evidence for a once weekly DDP chemoradiation regimen. For MFS at 4 yrs., DDP/5 FU-HART is superior to MMC/5 FU HART at equal levels of acute and late radiation sequelae for both treatment arms. No significant differences were seen yet for OS, PFS or LRC. Chemoradiation with weekly DDP/5-FU or MMC/5-FU shows excellent compliance rates and can easily compete with other concurrent chemo- or bio-radiation schedules including induction TPF followed by radiation.

Post-hoc analyses of overall survival (OS) and progression-free survival (PFS) in the TRIO-013/LOGiC trial of lapatinib (L) in combination with capecitabine plus oxaliplatin (CapeOx).

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 133-133
Author(s):  
Yung-Jue Bang ◽  
Shukui Qin ◽  
Hyun-Choel Chung ◽  
Jian-Ming Xu ◽  
Joon Oh Park ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Phase Iii ◽  
Her2 Positive ◽  
Phase Iii Trial ◽  
Free Survival ◽  
South Korean ◽  
Asian Populations ◽  
Asian Patients ◽  
Secondary Endpoints ◽  
Post Hoc

133 Background: Results of the primary and secondary endpoints (OS and PFS, respectively) in the primary efficacy population for the randomized, phase III trial (TRIO-013/LOGiC; NCT00680901), conducted in patients with advanced, HER2-positive upper gastrointestinal adenocarcinoma were previously presented (Hecht JR et al, ASCO 2013). Differences in OS were non-significant between the lapatinib (CapeOx + L) and placebo (CapeOx + P) arms. In prespecified analyses, a treatment effect of L was observed in Asian (majority Chinese or South Korean) patients and patients <60 years (y) when comparing OS in the two arms. Methods: Here, we present the results of post-hoc analyses in TRiO-013/LOGiC which assessed OS, PFS and safety by age and by region. Results: In the Asian subgroups, median OS was longer with L compared with P (see Table). In the rest of the world (ROW) subgroups, median OS was longer in patients <60 y but shorter in patients ≥60 y with L compared with P (see Table). Similar findings were observed for PFS in the 4 subgroups (see Table).More adverse events (AEs) were observed in the Asian subgroups; overall, the incidence of AEs (by region) was similar between age subgroups. Conclusions: OS and PFS were improved in Asian patients (both age subgroups) and younger patients in ROW given CapeOx + L, compared with CapeOx + P. The lower OS and PFS observed in older patients in the ROW subgroups may have affected the overall data. Further trials with CapeOx + L in Asian populations are being considered. Clinical trial information: NCT00680901. [Table: see text]

ENGOT-ov54/Swiss-GO-2/MATAO including LOGOS (Low-Grade Ovarian cancer Sub-study): MAintenance Therapy with Aromatase inhibitor in epithelial Ovarian cancer—A randomized, double-blinded, placebo-controlled, multicenter phase III Trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS5598-TPS5598
Author(s):  
Viola A. Heinzelmann-Schwarz ◽  
Christian Kurzeder ◽  
Seraina Schmid ◽  
Natalie Gabriel ◽  
Andreas Mueller ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Maintenance Therapy ◽  
Maintenance Treatment ◽  
Progression Free Survival ◽  
Final Analysis ◽  
Phase Iii ◽  
Low Grade ◽  
Phase Iii Trial ◽  
Free Survival ◽  
Double Blinded

TPS5598 Background: The prognosis of advanced epithelial ovarian cancer (OC) is poor with a relapse rate of 75% at 5 years. Some 80% of OC express estrogen receptor (ER). This is the first trial that wants to capitalize on this and prospectively evaluates letrozole, a potent aromatase inhibitor, as initial maintenance treatment for high and low grade OC. Methods: Eligible pts have primary OC, FIGO Stage II-IV with low or high grade serous or endometrioid histology, with (interval) debulking surgery, ECOG-status 0-2, Positivity (≥ 1%) for ER expression, and at least 4 cycles of platinum-based chemotherapy (neoadjuvant allowed). Pts are allowed to undergo concurrent maintenance treatment with bevacizumab and PARP inhibitors. Extensive quality of life (QoL) questionnaires via an App and physical activity measurements by a tracking device as well as G8 geriatric score, ESGO surgery questionnaire, and Charleson Comorbidity Index are routinely assessed. Primary objective is to evaluate the efficacy of letrozole maintenance therapy after standard surgical and chemotherapy treatment as measured by Progression Free Survival (PFS) compared to no maintenance therapy (placebo). Primary outcome is PFS, defined as time from date of first letrozole/placebo administration until date of progression or death by any cause. Stratification for high and low grade histologies and ER measurement is performed via a digital centralized pathology review process. Final analysis will be performed for the whole cohort and for the subgroup of low grade ovarian cancers (LOGOS subprotocol). Secondary objectives and outcomes are overall survival (OS), quality adjusted progression free survival (QAPFS), time to first subsequent treatment (TFST), quality adjusted time without symptoms (TWiST), and health related QoL. Study is designed as international, randomized (1:1 ratio), two-arm, multi-centric, double-blinded, placebo-controlled superiority phase III trial. In total, 528 pts will be randomly assigned to letrozole or placebo for 5 yrs or until unacceptable toxicity, progression of underlying disease, or study discontinuation. Final analysis is planned after 5 years without interval analysis and follow-up is collected for up to 10yr and for the low-grade cohort for up to 12yr. Clinical trial information: NCT04111978.

scholarly journals Randomized Phase III Trial Evaluating Spartalizumab Plus Dabrafenib and Trametinib for BRAF V600–Mutant Unresectable or Metastatic Melanoma

2022 ◽  
Author(s):  
Reinhard Dummer ◽  
Georgina V. Long ◽  
Caroline Robert ◽  
Hussein A. Tawbi ◽  
Keith T. Flaherty ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Metastatic Melanoma ◽  
Objective Response ◽  
Death Receptor ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Phase Iii Trial ◽  
Free Survival ◽  
End Point ◽  
Programmed Death

PURPOSE Preclinical data suggest the combination of an anti–programmed death receptor 1 antibody plus dabrafenib and trametinib to have superior antitumor activity compared with dabrafenib plus trametinib alone. These observations are supported by translational evidence suggesting that immune checkpoint inhibitors plus targeted therapy may improve treatment outcomes in patients with BRAF V600–mutant metastatic melanoma. COMBI-i is a phase III trial evaluating spartalizumab, an anti–programmed death receptor 1 antibody, in combination with dabrafenib and trametinib (sparta-DabTram), versus placebo plus dabrafenib and trametinib (placebo-DabTram) in patients with BRAF V600–mutant unresectable or metastatic melanoma. METHODS Patients received spartalizumab 400 mg intravenously every 4 weeks plus dabrafenib 150 mg orally twice daily and trametinib 2 mg orally once daily or placebo-DabTram. Participants were age ≥ 18 years with unresectable or metastatic BRAF V600–mutant melanoma. The primary end point was investigator-assessed progression-free survival. Overall survival was a key secondary end point (ClinicalTrials.gov identifier: NCT02967692 ). RESULTS At data cutoff (July 1, 2020), the median progression-free survival was 16.2 months (95% CI, 12.7 to 23.9 months) in the sparta-DabTram arm versus 12.0 months (95% CI, 10.2 to 15.4 months) in the placebo-DabTram arm (hazard ratio, 0.82 [95% CI, 0.66 to 1.03]; P = .042 [one-sided; nonsignificant]). The objective response rates were 69% (183 of 267 patients) versus 64% (170 of 265 patients), respectively. Grade ≥ 3 treatment-related adverse events occurred in 55% (146 of 267) of patients in the sparta-DabTram arm and 33% (88 of 264) in the placebo-DabTram arm. CONCLUSION The study did not meet its primary end point; broad first-line use of sparta-DabTram is not supported by these results. Further biomarker-driven investigation may identify patient subpopulations who could benefit from checkpoint inhibitor plus targeted therapy combinations.

Phase III Trial of Infusional Fluorouracil, Leucovorin, Oxaliplatin, and Irinotecan (FOLFOXIRI) Compared With Infusional Fluorouracil, Leucovorin, and Irinotecan (FOLFIRI) As First-Line Treatment for Metastatic Colorectal Cancer: The Gruppo Oncologico Nord Ovest

2007 ◽  
Vol 25 (13) ◽  
pp. 1670-1676 ◽  
Author(s):  
Alfredo Falcone ◽  
Sergio Ricci ◽  
Isa Brunetti ◽  
Elisabetta Pfanner ◽  
Giacomo Allegrini ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Peripheral Neurotoxicity ◽  
Phase Iii Trial ◽  
Free Survival ◽  
Secondary Resection ◽  
Phase Iii Study ◽  
Grade 3

Purpose The Gruppo Oncologico Nord Ovest (GONO) conducted a phase III study comparing fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI [irinotecan 165 mg/m2 day 1, oxaliplatin 85 mg/m2 day 1, leucovorin 200 mg/m2 day 1, fluorouracil 3,200 mg/m2 48-hour continuous infusion starting on day 1, every 2 weeks]) with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI). Methods Selection criteria included unresectable metastatic colorectal cancer, age 18 to 75 years, and no prior chemotherapy for advanced disease. The primary end point was response rate (RR). Results A total of 244 patients were randomly assigned. An increase of grade 2 to 3 peripheral neurotoxicity (0% v 19%; P < .001), and grade 3 to 4 neutropenia (28% v 50%; P < .001) were observed in the FOLFOXIRI arm. The incidence of febrile neutropenia (3% v 5%) and grade 3 to 4 diarrhea (12% v 20%) were not significantly different. Responses, as assessed by investigators, were, for FOLFIRI and FOLFOXIRI, respectively, complete, 6% and 8%; and partial, 35% and 58%, (RR, 41% v 66%; P = .0002). RR confirmed by an external panel was 34% versus 60% (P < .0001). The R0 secondary resection rate of metastases was greater in the FOLFOXIRI arm (6% v 15%; P = .033, among all 244 patients; and 12% v 36%; P = .017 among patients with liver metastases only). Progression-free survival (PFS) and overall survival (OS) were both significantly improved in the FOLFOXIRI arm (median PFS, 6.9 v 9.8 months; hazard ratio [HR], 0.63; P = .0006; median OS, 16.7 v 22.6 months; HR, 0.70; P = .032). Conclusion The FOLFOXIRI regimen improves RR, PFS, and OS compared with FOLFIRI, with an increased, but manageable, toxicity in patients with metastatic colorectal cancer with favorable prognostic characteristics. Further studies of FOLFOXIRI in combination with targeted agents and in the neoadjuvant setting are warranted.

scholarly journals Application of Circulating Cell-Free Tumor DNA Profiles for Therapeutic Monitoring and Outcome Prediction in Genetically Heterogeneous Metastatic Melanoma

2019 ◽  
pp. 1-10 ◽  
Author(s):  
Renáta Váraljai ◽  
Kilian Wistuba-Hamprecht ◽  
Teofila Seremet ◽  
Joey Mark S. Diaz ◽  
Jérémie Nsengimana ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Metastatic Melanoma ◽  
Disease Progression ◽  
Progression Free Survival ◽  
Mitogen Activated Protein Kinase ◽  
Quantitative Detection ◽  
Early Assessment ◽  
Free Survival ◽  
Mitogen Activated Protein ◽  
Tumor Dna

PURPOSE Circulating cell-free tumor DNA (ctDNA) reflects the heterogeneous spectrum of tumor-specific mutations, especially in systemic disease. We validated plasma-based assays that allow the dynamic quantitative detection of ctDNA as a prognostic biomarker for tumor load and prediction of therapy response in melanoma. MATERIALS and METHODS We analyzed plasma-derived ctDNA from a large training cohort (n = 96) of patients with advanced-stage melanoma, with assays for the BRAFV600E and NRASQ61 driver mutations as well as TERTC250T and TERTC228T promoter mutations. An independent patient cohort (n = 35) was used to validate the utility of ctDNA monitoring under mitogen-activated protein kinase–targeted or immune checkpoint therapies. RESULTS Elevated plasma ctDNA level at baseline was an independent prognostic factor of disease progression when compared with serum S100 and lactate dehydrogenase levels in multivariable analyses (hazard ratio [HR], 7.43; 95% CI, 1.01 to 55.19; P = .05). The change in ctDNA levels during therapy correlated with treatment response, where increasing ctDNA was predictive for shorter progression-free survival (eg, for BRAFV600E ctDNA, HR, 3.70; 95% CI, 1.86 to 7.34; P < .001). Increasing ctDNA levels predicted disease progression significantly earlier than did routine radiologic scans ( P < .05), with a mean lead time of 3.5 months. NRAS-mutant ctDNA was detected in a significant proportion of patients with BRAF-mutant tumors under therapy, but unexpectedly also at baseline. In vitro sensitivity studies suggested that this represents higher-than-expected intratumoral heterogeneity. The detection of NRASQ61 ctDNA in baseline samples of patients with BRAFV600E mutation who were treated with mitogen-activated protein kinase inhibitors significantly correlated with shorter progression-free survival (HR, 3.18; 95% CI, 1.31 to 7.68; P = .03) and shorter overall survival (HR, 4.08; 95% CI, 1.57 to 10.58; P = .01). CONCLUSION Our results show the potential role of ctDNA measurement as a sensitive monitoring and prediction tool for the early assessment of disease progression and therapeutic response in patients with metastatic melanoma.

Efficacy of Daratumumab Based Regimens Compared to Standard of Care for Transplant Ineligible Newly Diagnosed Multiple Myeloma in Phase III Clinical Trials: A Meta-Analysis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 32-33
Author(s):  
Zahoor Ahmed ◽  
Karun Neupane ◽  
Rabia Ashraf ◽  
Amna Khan ◽  
Moazzam Shahzad ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Standard Care ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Control Group ◽  
Two Phase ◽  
Phase Iii Trial ◽  
Free Survival ◽  
Phase Iii Clinical Trials

Introduction: Daratumumab (Dara) is a human anti-CD38 monoclonal antibody approved for multiple myeloma (MM) treatment. Dara has a promising efficacy and a favorable safety profile in newly diagnosed MM (NDMM) patients. This study is focused on the efficacy and safety of Dara when added to the standard care regimen in transplant ineligible NDMM in phase III clinical trials. Methods: We performed a comprehensive database search on four major databases (PubMed, Embase, Cochrane, and Clinicaltrials.gov). Our search strategy included MeSH (Medical Subject Headings) terms and key words for multiple myeloma and Dara including trade names and generic names from date of inception to May 2020. Initial search revealed 587 articles. After excluding review articles, duplicates, and non-relevant articles, two phase III clinical trials were included which reported overall response rate (ORR), and progression free survival (PFS) of transplant ineligible NDMM patients with Dara addition to standard care regimen. Odds ratios (OR) of ORR were computed and hazard ratios (HR) of PFS (along with 95% confidence intervals; CI) were extracted to compute a pooled HR using a fixed effect model in RevMan v.5.4. Results: A total of 1453 transplant ineligible NDMM patients were enrolled and evaluated in two phase III randomized clinical trials. Seven hundred and eighteen patients were in Dara group and 735 patients were in control group. Bahlis et al. (2019) studied Dara + lenolidamide (R) and dexamethasone (d) vs Rd in NDMM pts (n=737) in MAIA phase III trial. Similarly, Mateos et al. (2018) reported the role of Dara + bortezomib (V) + melphalan (M), and prednisone (P) vs VMP in NDMM pts (n=706) in a phase III trial (Alcyone). A pooled analysis of these phase III trials showed ORR (OR: 3.26, 95% CI 2.36-4.49; p &lt; 0.00001, I2 = 0%), and progression free survival (PFS) (HR: 0.53, 95% CI 0.43-0.65; p &lt; 0.00001, I2 = 0%). Achievement of minimal residual disease (MRD) negative status was significant in Dara based regimen as compared to control group (OR: 4.49, 95% CI 3.31-6.37; p &lt; 0.00001, I2 = 0%). Dara addition to standard care regimen (Rd and VMP) decreased the risk of progression/death to 42% (HR: 0.58, 95% CI 0.48-0.70; p &lt; 0.00001, I2 = 0%). The addition of Dara increased the risk of neutropenia (OR: 1.41, 95% CI 1.07-1.85; p &lt; 0.02, I2 = 44%), and pneumonia (OR: 2.25, 95% CI 1.54-3.29; p &lt; 0.0001, I2 = 37%) vs control group. However, decreased risk of anemia (OR: 0.64, 95% CI 0.49-0.85: p &lt; 0.002, I2=30%) was observed in Dara group vs control group (Figure 1). Conclusion: Addition of Dara to the standard care regimen for transplant ineligible NDMM achieved the surrogate end points with improved efficacy and MRD negative status with manageable toxicity. However, data from more randomized controlled trials is needed. Table Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

Subgroup analysis of efficacy and safety analysis of a randomized, double-blinded controlled phase II study of STA-4783 in combination with paclitaxel in patients with metastatic melanoma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 8528-8528 ◽  
Author(s):  
S. O'Day ◽  
R. Gonzalez ◽  
D. Lawson ◽  
R. Weber ◽  
L. Hutchins ◽  
...  
Keyword(s):  
Adverse Events ◽  
Metastatic Melanoma ◽  
Subgroup Analysis ◽  
Single Agent ◽  
Study Drug ◽  
Progression Free Survival ◽  
Additional Treatment ◽  
Phase Iii ◽  
Rapid Progression ◽  
Double Blinded

8528 Background: STA-4783 (S), an inducer of heat shock protein 70 (hsp70) is a bis-thiobenzoylhydrazide compound. S leads to up-regulation of hsp70 in tumor cell lines. Xenograft models of solid tumors showed synergistic anti-tumor activity in combination with paclitaxel (P). The combination P + S, in phase I and II studies, showed dose-related hsp70 induction (evidence of biological activity) and tolerability. Methods: Eligibility was based on a diagnosis of metastatic cutaneous melanoma, ECOG <=2, and prior treatment with 1 or no chemotherapy regimens. A total of 81 patients (pts) were randomized 2:1 (P 80 mg/m2 + S 213 mg/m2:P 80 mg/m2) 3 weeks out of 4 at 21 US clinical sites. The primary endpoint was progression free survival (PFS); secondary endpoints were response rate (RR), and adverse events (AEs). Results: Based on intent-to-treat analysis, the median PFS was 3.68 months (m) for P + S vs. 1.84 m in the P only arm (p=.035). RR was 15.1% in the P + S arm and 3.6% in the P arm. Subgroup analysis showed chemo- naive pts (n=23) with P + S showed a median PFS of 8.28 m vs. 2.40 in the P arm (n=9). For pts with 1 prior chemotherapy, (n=29), PFS on P + S was 3.12 m vs. 1.77 m on P (n=19). Of 19 pts who crossed over at progression, data are available for 14. PFS ranged from 0.72 to 5.5 m. Three of the 14 evaluable pts treated with P alone had rapid progression (0.95, 1.6, and 1.7 m) then significant inversion of the time to progression with the addition of S to P (2.3, 5.5, and 4.2 m) suggesting study drug effect. Scans were done at identical intervals (8 weeks). The proportion of pts with AEs of grade 3 or higher was 54% (n=52) in the P + S group and 57% in the P group (n=28); pts on P received a median of 2 cycles, while pts in the P + S group received a median of 4. Adverse events leading to discontinuation were low in both groups: 10% for the P + S, and 14% for P. Conclusions: The addition of S to P showed an increase in PFS vs. P alone particularly in chemo-naïve pts. A few pts failing single agent P appeared to benefit from P + S. Despite the additional treatment duration in the P + S group the drugs were well- tolerated, and showed mainly P related adverse events. A phase III study is planned to confirm a role for P + S in metastatic melanoma. [Table: see text]

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