Up-to-Date Tailored Systemic Treatment in Pancreatic Ductal Adenocarcinoma

Table 2

Selected clinical trials targeting desmoplastic stromal components in metastatic pancreatic ductal adenocarcinoma.

Target	Reference/trial number	Intervention	Phase	Status		Endpoints	Results
Hedgehog	Catenacci et al. [102]; NCT01064622	Vismodegib+gemcitabine	Ib/II	Completed	Phase 1b: 7; Phase II: 106	PFS, OS, ORR, safety	(i) Phase Ib: no safety issues identified; (ii) Phase II: no significant difference in PFS, OS, and ORR
	Ko et al. [103]; NCT01383538	IPI-926+FOLFIRINOX	Ib	Completed	15	MTD, PFS, ORR, CA19-9 decline, safety	(i) MTD reached at 1 dose level below standard FOLFIRINOX; (ii) trAEs: LFT abnormalities, neuropathy, nausea, vomiting, and diarrhoea; (iii) ORR 67.7%; (iv) CA19-9 decline in 66.7% when elevated at baseline
	Richards et al. [104]; NCT01130142	IPI-926+gemcitabine	Ib	Completed	16	Safety, MTD, OS, PK, PFS, TTP, ORR	(i) MTD IPI-926 160 mg OD; (ii) No IPI-926-related serious AEs; (ii) Median PFS >7 months
FAK	Aung et al. [105]; NCT02428270	GSK002256098+trametinib	II	Ongoing	16	ORR, safety, PFS	(i) PD as best tumour response in 10/11 and SD in 1/11 evaluable patients; (ii) Median PFS 1.6 months (95% CI 1.5-1.8); (iii) Median OS 3.6 months (95% CI 2.7-not reached); (iv) No trAEs
	NCT02546531 [106]	Defactinib+gemcitabine	I	Ongoing	N/A	RP2D, ORR, PFS, OS	N/A
Wnt-β-catenin	Ko et al. [107]; NCT01764477	PRI-724+gemcitabine	Ib	Completed	20	MTD, PK, pharmacodynamics, ORR	(i) MTD not reached; (ii) trAEs: abdominal pain, neutropenia, anaemia, fatigue, and elevated ALP; (iii) No DLTs; (iv) SD as best response in 8 patients (40%); (v) Median months
	Dotan et al. [108]; NCT02050178	Ipafricept (IPA)+gemcitabine/nab-paclitaxel	Ib	Completed	26	Safety, MTD, PK	(i) IPA-related AEs in ≥20% of patients: fatigue, nausea, vomiting, anorexia, and pyrexia; (ii) IPA-related AEs: AST elevation, nausea, maculopapular rash, vomiting, and WBC decrease; (iii) No DLTs or fragility fractures; (iv) PR in 9/26 evaluable patients (34.6%); (v) SD in 12/26 patients (46.2%); (vi) Study closed due to termination of the programme by sponsor; (a) Median PFS 5.9 months (95% CI 3.4-18.4); median OS 9.7 months (95% CI: 7.0-14) at data cut-off
PEGPH20	Hingorani et al. [67]; NCT01839487	PEGPH20+gemcitabine/nab-paclitaxel	II	Completed	279	PFS, ORR, OS, safety, PK	(i) Overall median PFS 6.0 months (PAG) vs. 5.3 months (AG) (HR 0.73; 95% CI, 0.53 to 1.00); (ii) In HA-high subgroup: (a) Median PFS 9.2 months (PAG) vs. 5.2 months (AG) (HR 0.51; 95% CI, 0.26 to 1.00; ); (b) Median OS 11.5 vs. 8.5 months (HR 0.96; 95% CI, 0.57 to 1.61); (c) ORR 46% (PAG) vs. 34% (AG); (iii) No significant difference in TE events with LMWH prophylaxis; (iv) Grade 3/4 trAEs: muscle spasms, neutropenia, myalgia
	NCT02715804 [109]	PEGPH20+gemcitabine/nab-paclitaxel	III	Ongoing	N/A	OS, PFS, ORR, DOR, safety	N/A
	Ramanathan et al. [68]; NCT01959139	PEGPH20+mFOLFIRINOX	II	Completed	114	OS, PFS, ORR, safety	(i) HR 2.07 in favour of control arm at interim futility analysis; (ii) Median OS mFOLFIRINOX vs. combination: 14.4 months (95% CI, 10.1 to 15.7 months) vs. 7.7 months (95% CI, 4.6 to 9.3 months); (iii) Grade 3/4 trAEs significantly higher in combination arm (OR 2.7; 95% CI, 1.1 to 7.1)
Hypoxia	Borad et al. [110]; NCT01144455	TH302+gemcitabine	II	Completed	214	PFS, OS, ORR, change in CA19-9, PS, and pain score	(i) Median PFS combination vs. gemcitabine: 5.6 vs. 3.6 months (HR 0.61; 95% CI, 0.43 to 0.87; ); (ii) TH302-related AEs: skin and mucosal toxicities and myelosuppression; unrelated to treatment discontinuation
	Van Custem et al. [111]; NCT01746979	TH302+gemcitabine	III	Completed	693	OS, PFS	(i) Median OS: 8.7 months (TH302+gemcitabine) vs. 7.6 months (gemcitabine+placebo) (, 95% CI 0.71-1.01, ); (ii) Median PFS: 5.5 months (TH302+gemcitabine) vs. 3.7 months (gemcitabine+placebo) (, 95% CI: 0.65-0.92, ); (iii) Similar safety profile between both arms
Angiogenesis	Kindler et al. [112]	Bevacizumab+gemcitabine	III	Completed	602	OS, PFS, ORR, safety	(i) No significant difference in median OS and PFS; (ii) Grade 3/4 hypertension and proteinuria significantly higher in combination arm
	NCT03316599 [113]	INC280+AV-299+gemcitabine/nab-paclitaxel	I	Ongoing	N/A	MTD, ORR, PFS, safety	N/A

References marked with denote results derived from published abstracts. Abbreviations: AE: adverse event; AG: gemcitabine/nab-paclitaxel; CBR: clinical benefit response; CI: confidence interval; DLT: dose-limiting toxicities; DOR: duration of response; HA-high: hyaluronan-high; HR: hazard ratio; MTD: maximum tolerated dose; OR: odds ratio; ORR: overall response rate; OS: overall survival; PAG: PEGPH20+gemcitabine/nab-paclitaxel; PD: progressive disease; PFS: progression-free survival; PK: pharmacokinetics; PR: partial response; RP2D: recommended phase 2 dose; SD: stable disease; trAEs: treatment-related adverse events; TTP: time to tumour progression.