Phase I clinical trial of the Src inhibitor dasatinib with dacarbazine in metastatic melanoma

Algazi, Alain P.; Weber, Jeffrey S.; Andrews, Stephanie; Urbas, P.; Münster, Pamela N.; DeConti, Ronald C.; Hwang, Jimmy J.; Sondak, Vernon K.; Messina, Jane L.; McCalmont, Timothy H.; Daud, Adil

doi:10.1038/bjc.2011.514

Cited by 34 publications

(30 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…QTc prolongation was frequent (>5% of patients experiencing CTCAE scale grade I QTc prolongation) in patients treated with dasatinib, vandetanib, sorafenib, or sunitinib. Dasatinib is used to treat hematological malignancies and has been associated with QTc prolongation in 8% of treated patients (range, 1%–70%), but QTc >500 ms was seen only in <1% 13, 18, 20, 21, 22, 25, 32, 40, 42, 75…”

Section: Resultsmentioning

confidence: 99%

Incidence, Diagnosis, and Management of QT Prolongation Induced by Cancer Therapies: A Systematic Review

Porta‐Sánchez

Gilbert

Spears

et al. 2017

JAHA

159

142

View full text Add to dashboard Cite

BackgroundThe cardiovascular complications of cancer therapeutics are the focus of the burgeoning field of cardio‐oncology. A common challenge in this field is the impact of cancer drugs on cardiac repolarization (ie, QT prolongation) and the potential risk for the life‐threatening arrhythmia torsades de pointes. Although QT prolongation is not a perfect marker of arrhythmia risk, this has become a primary safety metric among oncologists. Cardiologists caring for patients receiving cancer treatment should become familiar with the drugs associated with QT prolongation, its incidence, and appropriate management strategies to provide meaningful consultation in this complex clinical scenario.Methods and ResultsIn this article, we performed a systematic review (using Preferred Reporting Items of Systematic Reviews and Meta‐Analyses (PRISMA) guidelines) of commonly used cancer drugs to determine the incidence of QT prolongation and clinically relevant arrhythmias. We calculated summary estimates of the incidence of all and clinically relevant QT prolongation as well as arrhythmias and sudden cardiac death. We then describe strategies to prevent, identify, and manage QT prolongation in patients receiving cancer therapy. We identified a total of 173 relevant publications. The weighted incidence of any corrected QT (QTc) prolongation in our systematic review in patients treated with conventional therapies (eg, anthracyclines) ranged from 0% to 22%, although QTc >500 ms, arrhythmias, or sudden cardiac death was extremely rare. The risk of QTc prolongation with targeted therapies (eg, small molecular tyrosine kinase inhibitors) ranged between 0% and 22.7% with severe prolongation (QTc >500 ms) reported in 0% to 5.2% of the patients. Arrhythmias and sudden cardiac death were rare.ConclusionsOur systematic review demonstrates that there is variability in the incidence of QTc prolongation of various cancer drugs; however, the clinical consequence, as defined by arrhythmias or sudden cardiac death, remains rare.

show abstract

Section: Resultsmentioning

confidence: 99%

Incidence, Diagnosis, and Management of QT Prolongation Induced by Cancer Therapies: A Systematic Review

Porta‐Sánchez

Gilbert

Spears

et al. 2017

JAHA

159

142

View full text Add to dashboard Cite

show abstract

“…In a phase II trial in patients with unresectable melanoma of cutaneous, mucosal, or ocular origin, 2/36 patients (5.6%) of patients achieved a PR: 1 KIT- and 1 KIT+ with a primary subungual melanoma (K462E mutation) 34 . In a phase I trial of dasatinib plus dacarbazine, 4/29 evaluable patients (13.8%) had a partial response: all KIT- except for 1 NRAS mutation 35 .…”

Section: Discussionmentioning

confidence: 99%

A phase 2 trial of dasatinib in patients with locally advanced or stage IV mucosal, acral, or vulvovaginal melanoma: A trial of the ECOG‐ACRIN Cancer Research Group (E2607)

Kalinsky

Lee

Rubin

et al. 2017

Cancer

100

View full text Add to dashboard Cite

Purpose KIT-directed tyrosine kinase inhibitors (TKIs), such as imatinib, have demonstrated benefit in KIT mutant (KIT+) mucosal, acral, vulvovaginal, and chronically sun damaged (CSD) melanoma. Dasatinib has superior pre-clinical activity to other TKIs against cells with the most common KIT mutation, exon 11L576P. E2607 assessed dasatinib in patients (pts) with these melanoma subtypes. Patients and Methods Pts received dasatinib 70 mg orally twice daily. The primary objective for this two-stage phase II trial was response. Stage I was open to KIT+ and wild type (KIT-) mucosal, acral, and CSD melanoma (n=57). Stage II accrued only KIT+ tumors (n=30). To enrich for KIT+ tumors, vulvovaginal melanoma were added and CSD melanoma removed from eligibility. Secondary objectives included progression-free survival (PFS), overall survival (OS), and safety. Results From 5/09-12/10, the first stage enrolled 57 pts. Of the evaluable pts, 3/51 (5.9%) achieved a partial response (PR): all KIT-. Stage II closed early due to slow accrual (11/11-12/15). In stage II, 4/22 evaluable pts had a partial response (PR: 18.2%), median duration of 4.2 months. The median PFS was 2.1 months (n=73), 95% confidence interval (CI): 1.5-2.9 months. The median OS was 7.5 months (CI: 6.0-11.9 months). In exploratory analyses, no differences were seen in PFS or OS by KIT status or subtype. Dasatinib was discontinued due to adverse events in 9/75 pts (12%). Conclusions Dasatinib response among KIT+ melanoma pts was low. In view of its clinical activity, we recommend that imatinib remain the KIT TKI of choice for unresectable KIT+ melanoma.

show abstract

“…12 On the other hand, a phase 1 trial of dasatinib combined with dacarbazine in metastatic melanoma demonstrated the objective response rate to be 13.8 %, the clinical benefit rate to be 72.4 %, the 6-month progression-free survival to be 20.7 %, and the 12-month overall survival to be 34.5 %. 31 The benefit of dasatinib for patients harboring the c-kit mutation also has been reported. 12,32 In vitro, dasatinib combined with temozolomide significantly improved response in melanoma cell lines compared to either drug alone, 33 and dasatinib in combination with cisplatin was associated with reduced cell viability.…”

Section: Discussionmentioning

confidence: 94%

Src Family Kinase Inhibition as a Novel Strategy to Augment Melphalan-Based Regional Chemotherapy of Advanced Extremity Melanoma

et al. 2013

View full text Add to dashboard Cite

Background Src kinase inhibition has been shown to augment the efficacy of chemotherapy. Dasatinib, a dual Src/Abl kinase inhibitor approved for the treatment of CML, is under investigation as monotherapy for tumors with abnormal Src signaling, such as melanoma. The goal of this study was to determine if Src kinase inhibition using dasatinib could enhance the efficacy of regionally administered melphalan in advanced extremity melanoma. Methods The mutational status of c-kit and patterns of gene expression predictive of dysregulated Src kinase signaling were evaluated in a panel of 26 human melanoma cell lines. The effectiveness of dasatinib was measured by quantifying protein expression and activation of Src kinase, focal adhesion kinase, and Crk-associated substrate (p130CAS), in conjunction with in vitro cell viability assays using seven melanoma cell lines. Utilizing a rat model of regional chemotherapy, we evaluated the effectiveness of systemic dasatinib in conjunction with regional melphalan against the human melanoma cell line, DM443, grown as a xenograft. Results Only the WM3211 cell line harbored a c-kit mutation. Significant correlation was observed between Src-predicted dysregulation by gene expression and sensitivity to dasatinib in vitro. Tumor doubling time for DM443 xenografts treated with systemic dasatinib in combination with regional melphalan (44.8 days) was significantly longer (p = 0.007) than either dasatinib (21.3 days) or melphalan alone (24.7 days). Conclusions Systemic dasatinib prior to melphalan-based regional chemotherapy markedly improves the efficacy of this alkylating agent in this melanoma xenograft model. Validation of this concept should be considered in the context of a regional therapy clinical trial.

show abstract

Phase I clinical trial of the Src inhibitor dasatinib with dacarbazine in metastatic melanoma

Cited by 34 publications

References 50 publications

Incidence, Diagnosis, and Management of QT Prolongation Induced by Cancer Therapies: A Systematic Review

Incidence, Diagnosis, and Management of QT Prolongation Induced by Cancer Therapies: A Systematic Review

A phase 2 trial of dasatinib in patients with locally advanced or stage IV mucosal, acral, or vulvovaginal melanoma: A trial of the ECOG‐ACRIN Cancer Research Group (E2607)

Src Family Kinase Inhibition as a Novel Strategy to Augment Melphalan-Based Regional Chemotherapy of Advanced Extremity Melanoma

Contact Info

Product

Resources

About