Table 2:

Examples of clinical trials in which several nucleic acid molecules or other active moieties are being delivered by formulations that are also applied to deliver CRISPR/Cas 9 systems. No significant or severe treatment- or formulation-related toxicities were reported with most formulations.

Name/Clinical trial identifier (NCT) #	Therapeutic molecule	Target/purpose	Vehicle/vector	Route of administration, dose, and dosage ^a	Reported adverse events ^a
DOTAP:chol-TUSC2/ NCT00059605 (166, 167)	Plasmid DNA	Restoration of the activity of the tumor suppressor gene TUSC2/FUS1	DOTAP (cationic phospholipid) and cholesterol-based nanoparticles	Six dose levels ranging from 0.01 to 0.09 mg/kg given as a single intravenous infusion every 3 weeks.	Phase I study (in 31 patients with recurrent, and/or metastatic lung cancer) • IV injection of DOTAP:Chol-TUSC2 at escalating doses was found to be safe and well-tolerated. • The Maximum tolerated dose (MTD) was found to be 0.06 mg/kg. • Premedication with dexamethasone and diphenhydramine was mandated. • Dose-limiting toxicity (DLT) was detected in 2 patients, and manifested as grade 3 hypophosphatemia at 0.06 and 0.09 mg/kg.
PNT2258/ NCT01191775 NCT01733238 (168–171)	24-base single-stranded DNA oligodeoxy-nucleotide	BCL-2 oncogene	Smarticles® liposomes (approximately 130 nm, containing pH sensitive lipids that are cationic during manufacture and anionic during circulation).	Phase I study Intravenous infusion of 10 dose levels (ranging from 1 to 150 mg/m²) on an escalating dose design. Single dose was administered daily for 5 days on 21-day cycles.	Phase I study (in 22 patients with advanced metastatic solid tumors) • PNT2258 is well-tolerated with doses ranging from 1 up to 150 mg/m². • No unmanageable stage 3 or 4 adverse events. • No MTD was reached. • Decrease in lymphocytes and platelet count was manageable. • Dose limiting toxicity (DLT), manifested as a transient increase in aspartate aminotransferase, was reported with the highest dose (150 mg/m²) Phase II study (in patients with relapsed or refractory non-Hodgkin’s lymphoma) • PNT2258 was found to be well-tolerated. • No grade 3 or 4 adverse events reported.
SNS01-T/ NCT01435720 (115, 172, 173)	siRNA	Eukaryotic Translation Initiation Factor 5A (eIF5A)	Polyethyleneimine (PEI) nanoparticles	Intravenous infusion of 0.0125, 0.05, 0.2, and 0.375 mg/kg twice a week for six weeks.	Phase I/II study dose escalating study • Treatment-related adverse events were reported in all patients. • Grade 3 adverse events were reported in 50% of patients with no dose relationship found, with thrombocytopenia as the only grade 3 adverse event reported in one or more patient. • There was no reported treatment-related deaths, while one incident of DLT (grade 4 infusion reaction) was reported in one patient. • Treatment was discontinued and the treatment protocol was amended to add pretreatment with corticosteroids, antihistamine, and acetaminophen (obligatory), and opioid analgesic if clinically needed.
BC-819/ NCT01878188 NCT00826150 (174–177)	Plasmid DNA	H19 oncofetal gene	Polyethyleneimine (PEI)	Phase I/IIa study One Intraperitoneal injection/week for 6–9 weeks at maximum at doses up to 240 mg.	Phase I/IIa study (in 14 patients with recurrent ovarian/peritoneal cancer) • BC-819 was found to be safe and well-tolerated when doses up to 240 mg were administered intraperitoneally to cancer patients. • No dose limiting toxicity (DLT) was observed. • Grade 1 and 2 adverse events were observed in 4 patients. No grade 3 adverse events were recorded. Phase I/II study • Escalating-dose Intravesical administration was found to be safe and well-tolerated in patients with superficial bladder cancer.
Atu027/ NCT00938574 NCT01808638 (178–183)	siRNA	Protein kinase N3 (PKN3) gene in the vascular endothelial cells.	Cationic lipoplexes, containing fusigenic and PEGylated lipid components (AtuPLEX)	Phase I study One single dose received, followed by a twice weekly infusions over a 28-days cycle, according to a dose-escalation design with doses ranging from 0.001 to 0.336 mg/kg.	Phase I study (34 patients with advanced refractory solid tumors) • Atu027 was safe and well-tolerated in patients with advanced solid tumors. • No MTD was reached. • One patient showed DLT related to Atu027 administration (increased lipase, grade 3 adverse event). • Three deaths were reported, and none of them was attributed to Atu027. • Most adverse events reported were grade 1 and 2 (low). Ten percent of patients showed grade 3 adverse events. • No corticosteroid or antihistamine premedication was required. • Phase Ib/IIa study in combination with gemcitabine (23 patients with advanced pancreatic carcinoma) • The combination between Atu027 and gemcitabine was well-tolerated in patients with advanced pancreatic cancer. • Most adverse events were consistent with those reported with gemcitabine.
DCR-MYC/ NCT02110563 (184, 185)	siRNA	MYC oncogene	Encore® Lipid Nanoparticles	IV infusion on day 1 and day 8 over a 3-weeks cycle (week 3 is a rest period). Cycles continue until unacceptable toxicity emerges. The starting dose is 0.1 mg/kg with a dose escalation of 100, 50, or 25% increase depending on toxicity.	Phase I study • DCR-MYC doses up to 1 mg/kg were found to be safe and well-tolerated in advanced cancer patients. • Adverse events were all of low grade (grade 1 and 2). One patient developed a grade 3 infusion-related adverse event, and one patient experienced a grade 3 DLT (transient rise in AST). Efficacy results did not encourage further clinical investigation and thus the clinical development of DCR-MYC project was discontinued.
p28/ NCT00914914 NCT01975116 (186–189)	p28	Wild type and mutant P53	Cancer-cell killing cell penetrating peptide (p28), a synthetic 28-peptide fragment of azurin.	Phase I study in adult patients Intravenous infusion, three times/week for three weeks, followed by a rest period of 2 weeks. Dose escalation design was followed at doses of 0.83, 1.66, 2.5, 3.33, and 4.16 mg/kg.	Phase I study in adult patients with stage IV advanced solid tumors • Cumulative doses up to 140 mg/kg were well-tolerated and showed no immunogenicity (no antibody response to the p28 protein) or significant toxicity. • No MTD or No-Observed-Adverse-Effect-Level (NOAEL) was reached. • Only 15% of adverse events reported for all patients during the whole period of treatment (multiple visits) were of grade 3. None of them were considered directly-related to p28. Phase I study in pediatric patients with recurrent and progressive central nervous system tumors • In general, the treatment was well-tolerated in pediatric patients with solid CNS tumors. • The most-common treatment-related adverse event was grade 1 infusion reaction (transient). • One patient experienced 2 events of DLT (grade 4 neutropenia and thrombocytopenia).

The columns entitled ‘Route of administration, dose, and dosage’ and ‘Reported adverse events’ both report only selected examples of the clinical trials that employ the associated treatment, regardless of their status. They do not report information about all the clinical trials found in Clinicaltrials.gov, or any other source, about that particular treatment.