“Basket Combination Study of Inhibitors of DNA Damage Response, Angiogenesis and Programmed Death Ligand 1 in Patients With Advanced Solid Tumors”
This is a phase 2, single-centre, randomized, multi-cohort trial of subjects with advanced Mismatch Repair Proficient Colorectal Cancer (MMRp-CRC), Pancreatic Adenocarcinoma (PA), and Leiomyosarcoma (LMS). Subjects will be stratified based on their primary malignancy and enrolled into one of the following cohorts: - Cohort A: olaparib and durvalumab. - Cohort B: cediranib and durvalumab. Subjects will receive durvalumab through an intravenous line every 4 weeks. If subjects are assigned to the olaparib group, then they will take this pill twice a day continuously. If subjects are assigned to the cediranib group, then they will take this pill once a day for 5 consecutive days, and then have 2 consecutive days off, every week. Subjects will be enrolled in this trial to evaluate the changes in genomic and immune biomarkers in tumor, peripheral blood and stool samples, in addition to changes in radiomic profiles. About 90 people (45 subjects in each cohort) will be enrolled into this study at the Princess Margaret Cancer Centre.
Biological - Durvalumab
Durvalumab is a human immunoglobulin G (IgG)1 kappa monoclonal antibody directed against human PD-L1. Durvalumab selectively binds human PD-L1 with high affinity and blocks its ability to bind to PD-1 and cluster of differentiation (CD)80. The fragment crystallizable (Fc) domain of durvalumab contains a triple mutation in the constant domain of the IgG1 heavy chain that reduces binding to the complement component C1q and the Fc gamma receptors responsible for mediating antibody dependent cell me ...read more on ClinicalTrials.org
Drug - Olaparib
Olaparib (AZD2281) is a potent oral poly Poly (ADP-ribose) Polymerase (PARP) enzyme inhibitor (PARP-1, -2 and -3) that is being developed as an oral therapy, both as a monotherapy (including maintenance) and for combination with chemotherapy and other anti-cancer agents. Olaparib specifically traps PARP1 and PARP2 enzymes at sites of damaged DNA; the trapped PARP1- or PARP2-DNA complex is cytotoxic and produces clinical response. Although olaparib also binds to PARP3, recent investigations have ...read more on ClinicalTrials.org
Drug - Cediranib
Cediranib (AZD2171) is a potent oral small molecule Vascular Endothelial Growth Factor (VEGF) receptor tyrosine kinase inhibitor, specifically inhibiting all three VEGF receptors (VEGFR-1, -2 and -3). It has additional inhibitory activity against stem cell factor receptor tyrosine kinase, and less potency against platelet-derived growth factor receptor tyrosine kinases. Cediranib exerts its anti-angiogenic property by competitively inhibiting the ATP binding site on the VEGF receptors.
Basket Combination Study of Inhibitors of DNA Damage Response, Angiogenesis and Programmed Death Ligand 1 in Patients With Advanced Solid Tumors