Safety, pharmacokinetics, and pharmacodynamics of oral omaveloxolone (RTA 408), a synthetic triterpenoid, in a first-in-human trial of patients with advanced solid tumors

Figures & data

Table 1 Patient characteristics

Characteristic	Total (n=11)
Age, years
Median (range)	59.0 (43–78)
Gender, n (%)
Female	4 (36)
Race, n (%)
Caucasian	10 (91)
Black	1 (9)
Ethnicity, n (%)
Non-Hispanic	11 (100)
Cancer type, n (%)
Lung, adenocarcinoma	5 (45)
Lung, squamous uveal	3 (27)
Melanoma	3 (27)
AJCC stage, n (%)
IV	11 (100)
BMI, mg/m^2
Mean (SD)	27.7 (4.2)
Albumin, g/dL
Mean (SD)	4.1 (0.5)
Prior PD-1 or PD-L1 mAb, n (%)
Yes	6 (55)
No	5 (45)
Cohort, mg; n (%)
2.5	3 (27)
5	3 (27)
10	3 (27)
15*	2 (18)
Prior lines of systemic therapy
Median, range	4 (2–7)
Prior radiation, n (%)
Yes	8 (73)
No	3 (27)
Prior brain metastases, n (%)
Yes	5 (45)
No	6 (55)

Notes: All percentages are rounded and therefore may not exactly sum to one. Stage is assessed at the date of treatment.

* Dose level completed in two subjects.

Abbreviations: AJCC, American Joint Committee on Cancer; BMI, body mass index; mAb, monoclonal antibody; PD-1, programmed cell death protein 1.

Table 2 Omaveloxolone attributable AEs

Dose, mg	2.5		5		10		15		Total
Grade	1	2	1	2	1	2	1	2
Symptom
Chronic joint pain	1	–	–	–	–	–	–	–	1
Nausea or vomiting	1	–	–	–	–	–	–	–	1
Vomiting	1	–	–	–	–	–	–	–	1
Papular rash, arm and leg	1	–	–	–	–	–	–	–	1
Chronic leg swelling	1	–	–	–	–	–	–	–	1
Fatigue	1	–	–	–	–	–	–	–	1
Laboratory parameter
Anemia mean	2	–	–	–	–	–	–	–	1
LDH increased	1	–	–	–	–	–	–	–	1
ALT increased	–	–	–	–	–	1	–	–	1
AST increased	–	–	1	–	–	–	–	–	1
Alkaline phosphatase increased	–	–	1	–	1	–	–	–	2

Notes: No grade 3 or 4 drug-attributable adverse events were observed. Includes all possible, probable, or definite attributions.

Abbreviations: AEs, adverse events; ALT, alanine aminotransferase; AST, aspartate aminotransferase; LDH, lactate dehydrogenase.

Table 3 All AEs, regardless of attribution

Grade	1	2	3	4	Total
Symptom
Pain (all types)	2	2	2	–	6
Cough	1	1	–	–	2
Dyspnea	–	–	2	–	2
Pneumonia	–	–	2	–	2
Vomiting	1	1	–	–	2
Chronic leg swelling	1	–	–	–	1
Constipation	1	–	–	–	1
Dehydration	1	–	–	–	1
Depression	–	1	–	–	1
Dermatitis, scalp	1	–	–	–	1
Fall	1	–	–	–	1
Fever	1	–	–	–	1
Flu-like symptoms	1	–	–	–	1
Laryngeal hemorrhage	1	–	–	–	1
Nausea or vomiting	1	–	–	–	1
Papular rash, arm and leg	1	–	–	–	1
Pericardial effusion	–	1	–	–	1
Pulmonary hypertension	–	1	–	–	1
Wheezing	1	–	–	–	1
Laboratory parameter
Anemia mean	3	1	1	–	5
Alkaline phosphatase increased	2	–	–	–	2
Hypercalcemia	–	1	1	–	2
ALT increased	–	1	–	–	1
AST increased	–	–	1	–	1
BUN increased	1	–	–	–	1
Cholesterol increased	1	–	–	–	1
Hypoglycemia	1	–	–	–	1
Hypokalemia	–	1	–	–	1
Hyponatremia	1	–	–	–	1
LDH increased	1	–	–	–	1
Leukocytosis	1	–	–	–	1
Phosphorous increased	1	–	–	–	1
Triglycerides increased	1	–	–	–	1

Abbreviations: AEs, adverse events; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; LDH, lactate dehydrogenase.

Figure 1 Safety parameters over time.

Notes: (A) QTc by Frederica’s formula during omaveloxolone treatment are shown. Levels did not exceed normal range (<440 mseconds). (B) Overall plasma B-type natriuretic peptide levels during omaveloxolone treatment. Levels did not exceed normal range (<300 pg/mL). Values for all dose levels (n=11) are shown. Time 0 represents prior to dose. Circles represent mean with standard error.

Figure 2 Pharmacokinetic assessment of omaveloxolone.

Notes: (A) Drug concentration over time at days 1 and 28. Day 28 collections were missing for 15 mg cohort. (B) Maximum drug concentration in plasma. (C) Area under the plasma concentration–time curve was plotted against dose using linear regression for both day 1 and 28. Dotted lines represent 90% confidence interval. r_s, Spearman’s rho correlation coefficient with two-sided significance.

Table 4 Omaveloxolone pharmacokinetics

Dose, mg	2.5		5		10		15
Day	1	28	1	28	1	28	1	28
Evaluable (n)	3	3	3	3	3	3*	2**	n/a
AUC0–t (hours ng/mL)
Mean	27.6	44.8	31.6	63.7	114.4	188.3	183.5	–
SD	32.7	51.5	7.9	17.0	141.7	176.7	27.6	–
Tmax (hours)
Mean	3.3	2.9	2.3	2.5	2.0	3.0	3.5	–
SD	2.1	1	0.6	1.2	1.5	–	2.8	–
Cmax (ng/mL)
Mean	4.6	4.5	3.9	5.6	15.7	13.4	16.6	–
SD	7.8	4.6	2.1	1.8	34.5	9.7	6.9	–
T1/2 (hours)
Mean	10.2	21.2	8.9	19.7	9.2	19.8	8.7	–
SD	2.4	20.1	1.3	8.1	0.6	4.1	3.7	–

Notes: Averages represent geometric mean.

* One tube received broken at day 28.

** Dose level completed in two subjects.

Abbreviations: AUC_0–t, area under curve from time 0 to last; n/a, no samples available.

Figure 3 Effect of continuous oral omaveloxolone upon Nrf2 target genes.

Notes: mRNA expression was normalized to two housekeeping genes and then pre-dose level. (A) Expression over timepoints, 5 mg cohort example (n=3). Bars represent mean with standard error. *P<0.05 for Wilcoxon signed-rank test of whether post-dose timepoints exceeded normalized pre-dose level of 1. (B) Expression by dose level for samples collected at day 28, n=3 for each cohort. Bars represent mean with standard error. *P<0.05 for one-sided t-test for comparison between indicated groups.
Abbreviations: Ferritin H, ferritin heavy subunit; mRNA, messenger RNA; Nrf2, nuclear factor erythroid 2-related factor 2; PGDH, prostaglandin dehydrogenase 1.

Figure 4 Representative images of NT and iNOS from limited on-treatment tumor biopsies for two patients with metastatic melanoma.

Notes: (A) Punch skin biopsy at day +35 from patient in 10 mg cohort showed overall decrease in expression of nitration markers compared to baseline. (B) Bone metastasis biopsy at day +105 from patient in 5 mg cohort showed little difference in NT or iNOS expression compared to baseline. Archival bone samples were difficult to evaluate due to prior decalcification and scant tumor. Serial biopsies for additional patients were not available. Original magnification 4×.
Abbreviations: iNOS, inducible isoform of nitric oxide synthase; NT, nitrotyrosine.

Figure 5 Decrease in peripheral blood monocytic cells over time.

Notes: Absolute peripheral cell counts by automated differential during omaveloxolone treatment for all dose levels (n=11) are shown. Time 0 represents first day of dosing. Circles represent mean with standard error. *Denotes P=0.05 for one-sided t-test compared to baseline.

Figure 6 Patient outcome after treatment.

Notes: (A) Swimmers plot of survival for omaveloxolone-treated subjects according to modified RECIST. Numbers indicate dose level, in mg. (B) Spider plot showing change in target lesions by modified RECIST. *Target lesion noted as difficult to measure due to atelectasis. **Still alive during last assessment.
Abbreviations: LUSC, squamous lung cancer; LUAD, lung adenocarcinoma; MEL, melanoma; NSCLC, non-small cell lung cancer; RECIST, response evaluation criteria in solid tumor.

Table 5 Current clinical investigation of omaveloxolone

Trial	Indication	Size	Form	Phase	Start date	NCT#
MOTOR	Treatment of mitochondrial myopathy	56	Oral	2	4–2015	02255422
MOXIe	Treatment of Friedrich’s ataxia	56	Oral	2	1–2015	02255435
PRIMROSE	Radiation dermatitis in adjuvant breast cancer	187	Lotion	2	6–2014	02142959
REVEAL*	Treatment of metastatic melanoma	84	Oral	1/2	10–2014	02259231
GUARD	Prevention of post-operative corneal endothelial loss	304	Suspension	2	5–2014	02128113

Note:

* Combination trial of omaveloxolone with nivolumab or ipilimumab.

Abbreviation: NCT, national clinical trials identifier number.