Introduction
Methods
Patients
Study design
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Part A was a dose escalation study using galunisertib monotherapy administered initially to patients with advanced or metastatic cancer as a daily continuous dosing. Starting with Cohort 3 and for the remainder of the study, patients received galunisertib on an intermittent dose regimen of 14 days on/14 days off for a 28-day cycle.
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Part B was a safety study using galunisertib on an intermittent dose regimen at 160 mg/day (80 mg twice daily [BID]) and 300 mg/day (150 mg BID) in combination with lomustine given once every 6 weeks in patients with recurrent malignant glioma who had previously failed approved treatments.
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Part C was a relative bioavailability (RBA) crossover study conducted at only one center to assess two new formulations (publication in preparation). All patients were then eligible to continue on 300 mg/day dosing. In this part of the study, patients with different tumor histologies were eligible to participate; the majority of patients had glioma. The only results from Part C presented in this publication are the results of the T cell subset examination. Other results will be published elsewhere.
Study objectives
Treatment
Bioanalytical methods
Pharmacokinetic methods
Pharmacodynamics pSMAD2 ELISA
Flow cytometry for T cell subsets
Baseline biomarker assessments
Statistical analyses
Results
FHD study design and patient characteristics
Characteristics | Part A
N = 39 | Part B
N = 26 | Part C
N = 14 |
---|---|---|---|
Age, years | |||
Mean (SD) | 51.8 (14.88) | 44.5 (10.35) | 59.8 |
Median (Range) | 54 (22–77) | 43.5 (25–61) | 56.5 (34–76) |
Sex, n (%) | |||
Male | 30 (76.9) | 19 (73.1) | 5 (35.7) |
Female | 9 (23.1) | 7 (26.9) | 9 (64.3) |
ECOG, n (%) | |||
0 | 15 (38.5) | 3 (11.5) | 4 (28.6) |
1 | 19 (48.7) | 17 (65.4) | 8 (57.1) |
2 | 5 (12.8) | 6 (23.1) | 2 (14.3) |
Number of prior regimens, n (%) | |||
1 | 17 (43.6) | 7 (26.9) | 2 (14.3)a
|
2 | 13 (33.3) | 11 (42.3) | 4 (28.6)a
|
3 | 4 (10.3) | 7 (26.9) | 2 (14.3)a
|
> 3 | 5 (12.8) | 1 (3.8) | 1 (7.1)a
|
Patients with glioma only |
N = 32 |
N = 26 |
N = 9 |
Time from initial diagnosis to before first dose, median (range: earliest to most recent) in months | 22.1 (172.4−2.8) | 18 (154.6−7.0) | Not collected |
Glioma WHO, at study entry, n (%) |
n = 30 |
n = 26 | Not collected |
Grade I | 1 (3.3) | – | |
Grade II | 2 (6.7) | – | |
Grade III | 6 (20) | 4 (15.4) | |
Grade IV | 21 (70) | 22 (84.6) | |
Secondary grade IV | 6 (20) | 2 (7.7) | |
Primary grade IV | 15 (50) | 20 (76.9) | |
Tissue samples for deep sequencing |
n = 11 |
n = 10 | Not collected |
IDH1/2 mutation, n (%) | 3 (27.3) | 2 (20) |
Pharmacokinetic measures
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Part A (Fig. 1 and Table 2): Non-compartmental PK analysis was performed on 37 of the 39 patients treated in Part A: n = 3 in Cohort 1 (40 mg/day); n = 4 in Cohort 2 (80 mg/day); n = 15 in Cohort 3 (160 mg/day); n = 6 in Cohort 4 (240 mg/day); n = 9 in Cohort 5 (300 mg/day). Results showed rapid absorption of galunisertib, as demonstrated by measurable plasma concentrations for at least 48 h. The terminal half-life was approximately 8 h. At steady state, on Day 14, the median time to maximum concentration (tmax,ss) ranged from 0.5 to 2 h post dose, independent of dose. Formal assessment of time-linear kinetics was not possible, regardless of whether or not the observed exposures of AUC(0-∞) Day 1 and AUC(0-∞) Day 14 were similar. However, no accumulation of galunisertib in the 5 cohorts was observed over the 14-day BID dosing regimen. Both the maximum observed plasma concentration at steady state (Cmax,ss) and exposure increased with dose as indicated from the statistical analysis of the PK parameters. The estimated ratios of geometric means for the AUC(0-∞) and Cmax,ss between 40 and 300 mg daily (7.5-fold) were 5.61 (90 % confidence intervals [CI]: 3.80, 8.30) and 3.99 (90 % CI: 2.43, 6.54), respectively. For a doubling of dose, the fold increases for AUC(0-∞) and Cmax,ss were 1.81-fold with corresponding 90 % CI (1.58, 2.07) and 1.61-fold with 90 % CI (1.36, 1.91), respectively. This suggests dose-proportional PK for any doubling of dose within the studied dose range of 40–300 mg, particularly for AUC(0-∞). Within- and between-patient coefficients of variation were estimated as 29 and 42 %, respectively, for AUC(0-∞) at steady state, and 31 and 55 %, respectively, for Cmax,ss, all pooled across the 5 cohorts from the dose-proportionality analysis. A population PK model was developed based on data in Cohorts 1 through 5 [7]. The mean population CL of galunisertib was 38 L/h, and the steady state volume of distribution (Vss) was 210 L.Table 2Galunisertib plasma pharmacokinetic data and pharmacodynamic changes in patients from Part ATotal dose(mg/day)Number of patientscycle 1–2Observations mean (% CV), day 14, steady stateCycle 1Cycle 2Cmax, ss (ng/mL)AUC0,∞ (ng*h/mL)Cmax, ss (ng/mL)AUC0,∞ (ng*h/mL)403 - NA220 (92)518* (60)NANA804 - NA350 (44)1310* (41)NANA16013−9630 (58)2140 (52)790 (51)2430 (33)2405−2660 (44)3060 (49)520-a610-a2900-a2500-a3009−7990 (57)3730 (46)800 (58)2930 (63)Percent Inhibition of pSMAD2 (normalizedb) at the 160 mg/day cohort (Part A):Observed, fitted Percentage Inhibition of Normalizedb pSMAD2 – (N), (95 % CI)Day 1Day 12 or 150.546Post Dose26 %, 27 %(13), (−43, 62)5 %, 5 %(14), (−82, 51)−10 %, −10 %(14), (−112, 43)39 %, 34 %(15), (−26, 65)×
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Part B: Patients were administered lomustine in combination with galunisertib. PK profiles of galunisertib following administration of 160 mg/day (Cohort 6) and 300 mg/day (Cohort 7) on Days 6 and 7 were similar. Hence, co-administration of lomustine did not appear to alter the galunisertib PK profile.
Pharmacokinetics in patients receiving enzyme-inducing and nonenzyme-inducing anti-epileptic drugs and proton pump inhibitors
Pharmacodynamic evaluation
Changes in T cell subsets
Baseline tumor tissue evaluation
Patient ID | Tumor Grade | Cycles (n) | IDH1 | IDH2 | CIC | ATRX | TP53 | EGFR | CDKN2A | CDKN2B | CDK4 | RB1 | NF1 | PTEN | PIK3CA | MDM4 | PI3KR1 |
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Part A | |||||||||||||||||
R33 | Low | 29 (CR) | R132H | R215W | K567E | ||||||||||||
R23 | Secondary | 13 (PR) | R132H | K1045fs*1 | G245S | Amp | |||||||||||
R16 | Primary | 22 (PR) | A198fs*7 | Y16* | |||||||||||||
R19 | Primary | 46 (CR) | R156G & Q165P | C328fs*1 & R2411fs*10 | |||||||||||||
R21 | Primary | 40 (SD) | Y234H | splice | |||||||||||||
R34 | Low | 3 | R132H | K626fs*23 | R273C | ||||||||||||
R28 | Low | 3 | Amp | ||||||||||||||
R38 | Low | 3 | R108K + Amp | Loss | Loss | H1047R | |||||||||||
R20 | Primary | 2 | Loss | loss | E43fs*9 | ||||||||||||
R39 | Primary | 1 | L194R | loss | E462fs | ||||||||||||
R35 | Primary | 2 | |||||||||||||||
Part B | |||||||||||||||||
R54 | Low | 10 (PR) | R172K | A253T | G105S | splice | splice | P96S | |||||||||
R62 | Secondary | 12 (SD) | R132G | K305fs*40 | |||||||||||||
R53 | Secondary | 2 | Loss | Loss | C420R | ||||||||||||
R48 | Primary | 2 | A298T& Amp | Loss | R93W | Amp | |||||||||||
R51 | Primary | 2 | Amp | Loss | Loss | ||||||||||||
R61 | Primary | 2 | Amp | Loss | Loss | ||||||||||||
R64 | Primary | 4 | R324L + Amp | Loss | Loss | ||||||||||||
R47 | Primary | 2 | Amp | Amp | Amp | ||||||||||||
R50 | Primary | 2 | W91* | Amp | |||||||||||||
R52 | Primary | 1 | C242Y | Amp | Amp |
Reasons | Part A N = 39 n (%) | Part B N = 26 n (%) |
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Cycles on study treatment, median (range) | 2 (1–46) | 2 (1–22) |
Treatment response* |
n = 30 |
n = 26 |
CR/PR (%) | 5 (16.7) | 2 (7.7) |
SD ≥6 cycles | 1 (3.3) | 4 (15.4) |
CR/PR/SD ≥6 cycles | 6 (20.0) | 6 (23.1)* |
SD | 10 (33.3) | 5 (19.2) |
On study treatment at study closure in 2012 | 2 (6.7) | 1 (3.8) |
CR/PR/SD ≥6 cycles | 6 | 6* |
Primary | 3 | 2 |
Low grade/secondary glioma | 3 | 4 |
Treatment Responses by glioma grade and genetic mutation where tumor tissue was available (n = 21) | ||
IDH1/2 | Other | |
Secondary or low grade glioma (n = 8) | ||
Clinical Benefit | 4/8 | 0/8 |
No Clinical Benefit | 1/8 | 3/8 |
Primary glioma (n = 13) | ||
Clinical Benefit | 0/13 | 3/13 |
No Clinical Benefit | 0/13 | 10/13 |