Abstract:Lessons Learned.
Patients with hepatocellular carcinoma (HCC) often have limited therapeutic responses to the vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor sorafenib, which is standard of care in advanced HCC. Targeting the activin receptor‐like kinase 1 (ALK1) and VEGF pathways simultaneously by combining the ALK1 ligand trap dalantercept with sorafenib may result in more effective angiogenic blockade and delay tumor progression in patients with advanced HCC.
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“…The current study data suggest that the combination of axitinib plus dalantercept, although well tolerated, does not increase efficacy over axitinib alone in patients with pretreated RCC. Previous studies of dalantercept in individuals with squamous cell cancer of the head and neck, hepatocellular carcinoma, endometrial cancer, and ovarian cancer were conducted and did not demonstrate sufficient activity to proceed beyond phase 2 . Based on the lack of efficacy observed in the current study, the dalantercept program has been discontinued.…”
Section: Discussionmentioning
confidence: 87%
“…Previous studies of dalantercept in individuals with squamous cell cancer of the head and neck, hepatocellular carcinoma, endometrial cancer, and ovarian cancer were conducted and did not demonstrate sufficient activity to proceed beyond phase 2. [26][27][28][29] Based on the lack of efficacy observed in the current study, the dalantercept program has been discontinued.…”
Background
In a prior open‐label study, the combination of dalantercept, a novel antiangiogenic targeting activin receptor‐like kinase 1 (ALK1), plus axitinib was deemed safe and tolerable with a promising efficacy signal in patients with advanced renal cell carcinoma (RCC).
Methods
In the current phase 2, randomized, double‐blind, placebo‐controlled study, patients with clear cell RCC previously treated with 1 prior angiogenesis inhibitor were randomized 1:1 to receive axitinib plus dalantercept versus axitinib plus placebo. Randomization was stratified by the type of prior therapy. The primary endpoint was progression‐free survival (PFS). Secondary endpoints were PFS in patients with ≥2 prior lines of anticancer therapy, overall survival, and the objective response rate.
Results
Between June 10, 2014, and February 23, 2017, a total of 124 patients were randomly assigned to receive axitinib plus dalantercept (59 patients) or placebo (65 patients). The median PFS was not found to be significantly different between the treatment groups (median, 6.8 months vs 5.6 months; hazard ratio, 1.11 [95% CI, 0.71‐1.73; P = .670]). Neither group reached the median overall survival (hazard ratio, 1.39 [95% CI, 0.70‐2.77; P = .349]). The objective response rate was 19.0% (11 of 58 patients; 95% CI, 9.9%‐31.4%) in the dalantercept plus axitinib group and 24.6% (15 of 61 patients; 95% CI, 14.5%‐37.3%) in the placebo plus axitinib group. At least 1 treatment‐emergent adverse event of ≥grade 3 was observed in 59% of patients (34 of 58 patients) in the dalantercept group and 64% of patients (39 of 61 patients) in the placebo group. One treatment‐related death occurred in the placebo plus axitinib group.
Conclusions
Although well tolerated, the addition of dalantercept to axitinib did not appear to improve treatment‐related outcomes in previously treated patients with advanced RCC.
“…The current study data suggest that the combination of axitinib plus dalantercept, although well tolerated, does not increase efficacy over axitinib alone in patients with pretreated RCC. Previous studies of dalantercept in individuals with squamous cell cancer of the head and neck, hepatocellular carcinoma, endometrial cancer, and ovarian cancer were conducted and did not demonstrate sufficient activity to proceed beyond phase 2 . Based on the lack of efficacy observed in the current study, the dalantercept program has been discontinued.…”
Section: Discussionmentioning
confidence: 87%
“…Previous studies of dalantercept in individuals with squamous cell cancer of the head and neck, hepatocellular carcinoma, endometrial cancer, and ovarian cancer were conducted and did not demonstrate sufficient activity to proceed beyond phase 2. [26][27][28][29] Based on the lack of efficacy observed in the current study, the dalantercept program has been discontinued.…”
Background
In a prior open‐label study, the combination of dalantercept, a novel antiangiogenic targeting activin receptor‐like kinase 1 (ALK1), plus axitinib was deemed safe and tolerable with a promising efficacy signal in patients with advanced renal cell carcinoma (RCC).
Methods
In the current phase 2, randomized, double‐blind, placebo‐controlled study, patients with clear cell RCC previously treated with 1 prior angiogenesis inhibitor were randomized 1:1 to receive axitinib plus dalantercept versus axitinib plus placebo. Randomization was stratified by the type of prior therapy. The primary endpoint was progression‐free survival (PFS). Secondary endpoints were PFS in patients with ≥2 prior lines of anticancer therapy, overall survival, and the objective response rate.
Results
Between June 10, 2014, and February 23, 2017, a total of 124 patients were randomly assigned to receive axitinib plus dalantercept (59 patients) or placebo (65 patients). The median PFS was not found to be significantly different between the treatment groups (median, 6.8 months vs 5.6 months; hazard ratio, 1.11 [95% CI, 0.71‐1.73; P = .670]). Neither group reached the median overall survival (hazard ratio, 1.39 [95% CI, 0.70‐2.77; P = .349]). The objective response rate was 19.0% (11 of 58 patients; 95% CI, 9.9%‐31.4%) in the dalantercept plus axitinib group and 24.6% (15 of 61 patients; 95% CI, 14.5%‐37.3%) in the placebo plus axitinib group. At least 1 treatment‐emergent adverse event of ≥grade 3 was observed in 59% of patients (34 of 58 patients) in the dalantercept group and 64% of patients (39 of 61 patients) in the placebo group. One treatment‐related death occurred in the placebo plus axitinib group.
Conclusions
Although well tolerated, the addition of dalantercept to axitinib did not appear to improve treatment‐related outcomes in previously treated patients with advanced RCC.
“…6 ), and showed decreased levels of urine sodium and chloride levels in Alk1ΔEC−/− mice. Since urine albuminuria and serum electrolytes did not vary between C5Cre and Alk1ΔEC−-/− mice, changes in sodium and chloride levels in urine may be indicative of vascular hyperpermeability or early cardiac failure, which have been associated with Alk1 loss-of-function 17 , 34 – 36 . Figure 7 Effects of Alk1ΔEC homozygote deletion on renal function.…”
Section: Resultsmentioning
confidence: 98%
“…6), and showed decreased levels of urine sodium and chloride levels in Alk1ΔEC−/− mice. Since urine albuminuria and serum electrolytes did not vary between C5Cre and Alk1ΔEC−-/− mice, changes in sodium and chloride levels in urine may be indicative of vascular hyperpermeability or early cardiac failure, which have been associated with Alk1 loss-of-function 17,[34][35][36] . Even though complete Alk1 deletion did not result in glomerular filtration defects within the time-frame of these experiments, we evaluated whether it could result in early glomerular alterations which could predispose to the development of glomerular dysfunction.…”
Section: Evidence Of Urine Albumin Excretion and Hyperfiltration In Amentioning
Endothelial dysfunction has been shown to play an important role in the pathogenesis of glomerular damage during diabetic kidney disease (DKD). As such, a better understanding of the molecular mechanisms involved in glomerular endothelial dysfunctions could provide novel therapeutic strategies for the prevention of DKD. We have previously shown that Alk1/BMP9 signaling plays an important function to maintain vascular integrity in diabetic animals. As such, we evaluated the effects of Alk1 suppression on glomerular endothelial function in diabetic mice. In the present study, we used mice with conditional heterozygote deletion of Alk1 in the endothelium (Alk1ΔEC) to evaluate the role of Alk1 on kidney function during STZ-induced diabetes. DKD was investigated in diabetic control and Alk1ΔEC mice euthanized eight weeks after the onset of diabetes. We showed that Alk1 expression is reduced in the glomeruli of human DKD patients. While renal function was not altered in Alk1ΔEC non-diabetic mice, we showed that Alk1 haploinsufficiency in the glomerular endothelium leads to microalbuminuria, thickening of the glomerular basement membrane, glomerular apoptosis and podocyte loss in diabetic mice. These data suggest that Alk1 is important for the proper function of glomerular endothelial cells and that decreased Alk1 combined with chronic hyperglycemia can impair renal function.
“…Besides canonical (TGFBR1-dependent) signaling, TGF-β can also activate Smad1/5/8 (i.e., BMP-associated) pathways through activin receptor-like kinase 1 (ALK1) together with TGFBR2 (89). Indeed, ALK1-dependent signaling represents a potential alternative mechanism of TGF-β signaling in HCC, and the ALK1 inhibitor dalantercept is currently investigated in clinical trials in HCC patients (90). However, our study provides mechanistic evidence that the effects of TGF-β signaling on the NPY/Y5R axis in HCC are mediated via the canonical, TGFBR1-related pathway.…”
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