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The anti-retroviral agent, nelfinavir (N), demonstrated radiosensitising properties in pre-clinical models and showed promising activity in single arm phase I/II trials in combination with CRT for LAPC. RT dose escalation (BED10 >70) may be associated with improved survival. SCALOP2 was a phase 1/randomized phase II study. The phase I component established the MTD of nelfinavir in combination with capecitabine-based CRT following gemcitabine+nab-paclitaxel (GEMABX) induction chemotherapy in LAPC (previously reported). The 2 x 2 randomized phase II component evaluated whether (1) RT dose escalation from 50.4Gy/28 fractions [standard dose (SD)] to 60Gy/30 fractions [high dose (HD)], combined with capecitabine improved OS and (2) adding nelfinavir to CRT improved PFS.

Patients with unresectable, histologically/cytologically proven LAPC and WHO PS 0-1 received 3 cycles of induction GEMABX (standard dose and schedule) followed by restaging. Progression-free patients were randomized to 1 further cycle of GEMABX followed by A (SD+N), B (SD = control arm), C (HD +N), D (HD), or E (GEMABX x 2 cycles = calibration arm). CRT capecitabine dose was 830mg/m2 bd on days of RT, nelfinavir 1250mg bd started 7 days before CRT until completing CRT.

Between March 2016 and March 2020, 186 patients were recruited from 21 centres in the UK (phase 1=27; phase 2=159). 106/159 patients were randomized (A=19, B=26, C=19, D=27, E=15). Arm E closed in Nov 2019, taking into consideration data from the LAPACT trial. The ISDMC recommended closure of the nelfinavir arms in Feb 2020 due to futility. At the time of analysis, 64/91 patients randomized to CRT arms had died. Median OS was 15.6 mo (60% CI 14.3,18.2) in the SD arms and 16.9 mo (16.2, 17.7) in the HD arms, HR (60% CI) 1.11(0.89,1.38), adjusted one-sided p=Not significant (NS). Of the 76 patients eligible for randomization to N-containing arms, median PFS was 11.1 (10.3, 12.8) in the CRT-only arms (HR (60% CI) 1.84(1.47,2.3) and 10 mo (60% CI 9.9,10.2) in the CRT+N arms, adjusted one-sided p=NS. Secondary endpoints: Grade 3-4 serious adverse reactions during CRT were reported as follows: 5/45 (11.1%) in SD arms, 4/46 (8.7%) in HD arms, 5/38 (13.2%) in CRT+N arms and 4/38 (10.5%) in CRT-only arms. 1-year local progression (with/without metastasis) and local-only (no metastasis) progression rate was 33.3% and 26.7% (SD arms) and 23.9% and 15.2% (HD arms) respectively. Overall resection rate (11%) and quality of life were similar for all arms.

The addition of nelfinavir and/or RT dose escalation to 60Gy failed to improve outcomes in LAPC. RT dose escalation to 60Gy was well tolerated.