Abstract
BackgroundInduction chemotherapy followed by chemoradiation is a treatment option for patients with locally advanced pancreatic cancer (LAPC). However, overall survival is comparable to chemotherapy alone and local progression occurs in nearly half of all patients, suggesting chemoradiation strategies should be optimised. SCALOP-2 is a randomised phase II trial testing the role of radiotherapy dose escalation and/or the addition of the radiosensitiser nelfinavir, following induction chemotherapy of gemcitabine and nab-paclitaxel (GEMABX). A safety run-in phase (stage 1) established the nelfinavir dose to administer with chemoradiation in the randomised phase (stage 2).MethodsPatients with locally advanced, inoperable, non-metastatic pancreatic adenocarcinoma receive three cycles of induction GEMABX chemotherapy prior to radiological assessment. Those with stable/responding disease are eligible for further trial treatment. In Stage 1, participants received one further cycle of GEMABX followed by capecitabine-chemoradiation with escalating doses of nelfinavir in a rolling-six design. Stage 2 aims to register 262 and randomise 170 patients with responding/stable disease to one of five arms: capecitabine with high- (arms C + D) or standard-dose (arms A + B) radiotherapy with (arms A + C) or without (arms B + D) nelfinavir, or three more cycles of GEMABX (arm E). Participants allocated to the chemoradiation arms receive another cycle of GEMABX before chemoradiation begins. Co-primary outcomes are 12-month overall survival (radiotherapy dose-escalation question) and progression-free survival (nelfinavir question). Secondary outcomes include toxicity, quality of life, disease response rate, resection rate, treatment compliance, and CA19–9 response. SCALOP-2 incorporates a detailed radiotherapy quality assurance programme.DiscussionSCALOP-2 aims to optimise chemoradiation in LAPC and incorporates a modern induction regimen.Trial registrationEudract No: 2013–004968-56; ClinicalTrials.gov: NCT02024009.
Highlights
Induction chemotherapy followed by chemoradiation is a treatment option for patients with locally advanced pancreatic cancer (LAPC)
Current chemoradiation regimens have not demonstrated superior overall survival (OS) over chemotherapy alone [2, 3], local failure occurs in 40–60% of cases despite chemoradiation [4,5,6], and tumours are rarely down-staged to resectibility [1] or achieve pathological complete responses [5, 7]
Chemoradiation must be optimised to improve these outcomes, as studies have shown that nearly one-third of patients with LAPC die due to local progression rather than systemic spread [8], and local failure may be a predictor of early mortality (hazard ratio [Hazard ratio (HR)] = 2.15; 95% confidence interval (CI): 1.23–3.75, [4])
Summary
Study design and participants Stage 1 of SCALOP-2 was a single-arm, dose-finding study of nelfinavir with capecitabine-chemoradiation using the rolling-six design [23]. A DLT was defined as per CTCAE V4.03 during chemoradiation and within 1 week post-chemoradiation as: any toxicity grade ≥ 4, any non-haematological grade 3 nelfinavir- or treatment-related AE or laboratory abnormality that the investigator deemed clinically significant, an inability to tolerate at least 20 fractions of radiotherapy due to an AE, or any SAE severe enough to halt radiotherapy for ≥14 days before recommencement (excluding events such as disease progression/stent blockage). Participants without DLTs were evaluable if, during and ≤ 1 week after chemoradiation, they received at least 80% of the total intended (starting) dose of both nelfinavir and capecitabine, and at least 20 fractions of radiotherapy, and had completed the minimum safety evaluation requirements at each weekly clinic visit. If both radiotherapy arms have 49 or more participants surviving, survival, proportion of participants completing the protocol dose radiotherapy, and toxicities observed will be taken into consideration to choose the treatment arm to take
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