NCT03851614

Study of DNA Damage, Angiogenesis, and PD-L1 Inhibitors in Advanced Solid Tumors

Basket Combination Study of Inhibitors of DNA Damage Response, Angiogenesis and Programmed Death Ligand 1 in Patients With Advanced Solid Tumors

• Status: Active Not Recruiting
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 90 (estimated)
• Sponsor: University Health Network, Toronto · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

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.

Detailed description

The goal of this study is to evaluate the changes in genomic and immune biomarkers in tumor, peripheral blood and stool samples, in addition to changes in radiomic profiles, of subjects with advanced Mismatch Repair Proficient Coloretal Cancer (MMRp-CRC), Pancreatic Adenocarcinoma (PA), or Leiomyosarcoma (LMS) during combination treatment of durvalumab (inhibitor of PD-L1) with either olaparib (inhibitor of Poly (ADP-ribose) polymerase \[PARP\]) or cediranib (inhibitor of Vascular Endothelial Growth Factor Receptor \[VEGFR\] tyrosine kinases).

Conditions

• Mismatch Repair Proficient Colorectal Cancer
• Pancreatic Adenocarcinoma
• Leiomyosarcoma

Interventions

Type	Name	Description
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 mediated cytotoxicity.
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 suggested PARP-3 inhibition does not contribute towards anti-cancer activity.
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.

Timeline

• Start date: 2019-04-08
• Primary completion: 2027-01-01
• Completion: 2027-01-01
• First posted: 2019-02-22
• Last updated: 2026-02-09

Locations

1 site across 1 country: Canada