Prospective, randomised controlled trials (RCTs) provide the highest level of scientific clinical evidence and are the gold standard for comparative studies. However, RCTs typically have narrow eligibility criteria that limit recruitment and external validity, and are conducted at substantial per-patient cost. Clinical registries provide access to large pools of real world patients and infrastructure for collecting baseline variables, treatment and outcome data at far lower cost. By incorporating the important elements of a successful RCT, including prospective identification of eligible patients and random assignment of treatment, a clinical registry can provide the basis for a prospective registry-based randomised controlled trial (RRCT). Here, we describe the framework for ALT-TRACC, the first in a series of RRCTs supported by the Victorian Comprehensive Cancer Centre and designed to explore the feasibility of this approach in oncology. The Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) registry is a well-established multi-centre registry collecting clinicopathologic, treatment and outcome data for patients with metastatic colorectal cancer (mCRC), with almost 3000 patients enrolled across 32 Australian sites so far. In the ALT-TRACC study, patients with treatment-naïve mCRC who consent to participate will be randomised 1:1 to standard doublet chemotherapy versus alternating oxaliplatin- and irinotecan-based doublets. The rationale for this treatment approach is to increase efficacy by delaying the emergence of cell resistance and allowing exposure to all active chemotherapy agents in the first-line setting, while avoiding the toxicity of concurrent triplet chemotherapy. The initial choice of regimen and biologic therapy is at the treating clinician’s discretion. Site-based randomisation will be performed utilising Research Electronic Data Capture (REDCap) as a platform. Target accrual is 140 patients in the feasibility phase. ALT-TRACC has received ethics approval at two Victorian sites, with the first enrolled patient expected in the third quarter of 2018.