A first-in-human dose-escalation study
of the safety, pharmacokinetics (PK),
and pharmacodynamics (PD) of intravenous
BAL101553, a novel microtubule inhibitor,
in adult patients with advanced solid tumors.
L Rhoda Molife1, Judy King2, Alan Smith1, Manolo D'Arcangelo3, Nicholas Brown2,
Nikolaos Diamantis1, Heidi Lane4, Anne Schmitt Hoffmann4, Marc Engelhardt4,
Ruth Plummer3, and Rebecca Kristeleit2
1The
Royal Marsden Hospital/Institute of Cancer Research, Sutton, United Kingdom
2University College London Hospital, London, United Kingdom
3Newcastle University, Newcastle upon Tyne, United Kingdom
4 Basilea Pharmaceutica International Ltd, Basel, Switzerland
Disclosures
• This study (NCT01397929) is sponsored by Basilea
Pharmaceutica International Ltd, Basel, Switzerland. Data are
interim from an unlocked database and may be subject to
change
• Participating study centers and their staff receive funding from
CRUK and the ECMC network
BAL101553 - A Prodrug of BAL27862
• BAL101553 - pro-drug of the fully
synthetic small molecule BAL27862
• BAL101553 - lysine provides:
• water-solubility in physiological pH range
• favorable PK/PD features (efficiently cleaved)
• Pure aqueous formulation
• no solubilizing excipients
• ↓ adverse side-effects
• Animal studies:
• high oral bioavailability and efficacy
• BAL27862 largely distributed in all organs
BAL27862
3
BAL101553
(pro-drug))
• including the brain
BAL27862 - Binds the Colchicine Site of Tubulin
No MTA registered in oncology that binds the colchicine site
MTA: Microtubule targeting agent
4
BAL27862 - A Novel Microtubule Destabilizer
BAL27862 is a potent
microtubule destabilizer
s
p
control
s
p
BAL27862
10 µM
s
Phenotype distinct from
conventional agents
vinblastine
paclitaxel
colchicine
BAL27862
p
BAL27862
100 nM
s= unpolymerized (soluble) tubulin
p = polymerized tubulin
Interphase
non-dividing cell
Microtubules
DNA
5
Mitotic
dividing cell
BAL27862
mitotic phenotype
Treatment:
50 nM, 24 h
BAL27862 - Highly Potent with Broad Activity
• Potent anti-proliferative activity against a large panel of tumor
cell lines in vitro (low nM IC50 s) and mouse xenograft models
• Potent activity in tumor models resistant to standard MTAs
through:
•
•
•
•
Drug efflux pump (Pgp) overexpression
Aberrant expression of tubulin isotypes
Mutations in β-tubulin
Deregulated cell survival & checkpoint control pathways
• Activity in patient-derived tumor cells with intrinsic resistance
to taxanes
No other MTA has been reported to have a comparable profile
6
BAL101553 - Effects on Cell Survival, Proliferation
and Blood Vessel Density
Tumor model: H460 lung cancer xenografts
Treatment (IV): Day 1 & Day 4, sacrifice Day 5
Cell proliferation: Ki67
Vasculature: SMA
BAL101553
Vehicle
Tumor necrosis: H&E
7
Confirmed by tumor vessel
perfusion experiments
BAL101553 - Phase 1/2A Study Design
• Phase 1/2A (first-in-human) multicenter study:
• Phase 1: accelerated titration, dose escalation, advanced solid tumors
• Phase 2A: MTD expansion in:
•
•
•
•
•
•
colorectal
gastric /gastro-oesophageal junction
non-small cell lung cancer
ovarian (inc primary peritoneal)
pancreatic (including ampullary cancer)
triple-negative breast cancer
• Objectives:
• Define MTD and DLTs of BAL101553
• Define BAL101553/BAL27862 PK
• Explore efficacy; utility of biomarkers
8
BAL101553 - Phase 1/2A Study Design cont.
• Study treatment:
• IV BAL101553, 2-hour infusion, on Days 1, 8 and 15, q28 days
• Starting dose: 15 mg/m2
• Option for intra-patient dose-escalation
• Patients could continue BAL101553 until disease progression/unacceptable
toxicity
9
BAL101553 - Phase 1 Results: Patient Demographics
Patient demographics and baseline characteristics
N
Received at least one dose of BAL101553
24
Female/Male
12/12
ECOG: 0/1/2
11/13/0
Age (years) : median (min-max)
Number of prior treatment regimens : median (min-max)
Patients evaluable for efficacy (RECIST 1.1)
54.5 (29-80)
3 (1-6)
19
Tumor type
Colorectal
6
Ovarian/Peritoneal
3
NSCLC
2
Adrenocortical; Ampullary; Anal; Cervical; Cholangiocarcinoma; Chondrosarcoma;
Esophageal; Gastric; Laryngeal; Mesothelioma; Neuroendocrine; Small Bowel; Thymoma
1
• Six dose cohorts completed: 15 mg/m2, 30 mg/m2, 45 mg/m2, two cohorts of
60 mg/m2, and one cohort of 80 mg/m2
• 10Dose escalation completed with 21 evaluable patients
BAL101553: Adverse Drug Reactions
Dose level (mg/m2) [N]
Severity (CTACEv4)
Nausea
15 [1]
G1/2
1
G3
30/45 [6]
G1/2
G3
1
Vomiting
Hypertension
1
60 [10]
G1/2
G3
80 [7]
G1/2
G3
Any dose [24]
G1/2
6
7
15 (63%)
6
6
12 (50%)
1
4
6
1 (4%)
Fatigue
1
5
4
10 (42%)
Diarrhea
1
4
4
9 (38%)
3
3
1
8 (33%)
2
6
8 (33%)
Injection Site Reaction
1
Peripheral Neuropathy
Paraesthesia
Fever
Headache
1
1
2
1
2
1
4 (17%)
3
1
4 (17%)
MTD: 60 mg/m2
DLT: Grade 2-3 reversible gait disturbance at 80mg/m2
11
4 (17%)
G3
11 (46%)
BAL101553 - Plasma
Pharmacokinetic (PK) Results
• Dose-proportionality over
a dose range of 15-80 mg/m2
• t1/2 = 9-27 h
• AUCs of BAL27862 observed
in humans at 60 mg/m2 are up
to 3× above the AUC in dogs
and up to 1.5 × above the AUC
in rats at the respective MTDs.
• Intra/intersubject variability of
AUC was low or moderate.
12
BAL101553 - Tumor
Pharmacodynamic (PD) Results
• Peritoneal carcinoma patient (60 mg/m2)
• Analysis of post-dose (Cycle 1, Day 22) vs pre-dose tumor tissue
suggests an anti-vascular effect.
CD34+ staining
Pre-dose
13
Post-dose
BAL101553 – Tumor PD Results cont.
• Peritoneal carcinoma (60 mg/m2)
• Analysis of post-dose (Cycle 1, Day 22) vs pre-dose tumor tissue
suggests a focal anti-proliferative effect.
Ki67 staining
Pre-dose
14
Post-dose
BAL101553 – Tumor PD Results cont.
• Mesenchymal chondrosarcoma (60 mg/m2)
• Analysis of post-dose (Cycle 1, Day 22) vs pre-dose tumor tissue
suggests a profound anti-proliferative effect.
Ki67 staining
Pre-dose
15
Post-dose
BAL101553 – Clinical Activity
Days on study drug
Best objective response
in evaluable patients (N=19)
RECIST 1.1
N
Partial response
1
Stable disease (≥ 2 Cycles)
5
[Stable disease > 4 Cycles]
[2]
Progressive disease
16
13
1031 days
BAL101553 - Dose Response for Blood Pressure (BP)
• Untreated BP profiles in two patients at 60 mg/m2 and after dose
reduction to 30 mg/m2:
Patient 26-05
Systolic BP (mmHg)
End of Tmax
infusion
60 mg/m2
30
mg/m2
Time after start of infusion (h)
18
Systolic BP (mmHg)
Patient 26-06
End of
infusion
Tmax
60 mg/m2
30 mg/m2
Time after start of infusion (h)
BAL101553 - Preclinical Support for Further
Phase 2A Dose Evaluation
• Single-dose PK/PD analyses of subcutaneous H460 xenografted
tumors in mice treated with BAL101553:
• Vascular disruption: moderate at 10 mg/kg; complete at 25 mg/kg (MTD)
• BAL27862 tumor tissue Cmax: 7
̴ × higher at 10 mg/kg vs 25 mg/kg
• BAL27862 tumor tissue AUC: 1̴ .5× higher at 10 mg/kg vs 25 mg/kg
MTD dosing may not be ideal for optimal drug delivery to tumor
19
BAL101553 - Summary
• BAL101553 was tolerated up to MTD of 60 mg/m2, day 1,
8, 15 q28d
• Evidence of anti-tumor activity
• DLT:
• Grade 2-3 gait disturbance
• occurred with Grade 2 peripheral sensory neuropathy
20
BAL101553 - Summary cont.
• PD analyses of tumor biopsies
• pronounced vascular disrupting effects & anti-proliferative
effects
• PK dose-proportionality over a dose range of 15-80 mg/m2
• Transient Tmax-related BP elevations: vascular effects are driven by
peak plasma concentrations
• Sub-MTD dose may be preferred (cytotoxic with reduced
vascular effects)
21
BAL101553 – Ongoing and Future Studies
• Ongoing randomized Phase 2A study (MTD and 50%-MTD)
to determine the RP2D
– extensive analysis of PD and potential patient-stratification biomarkers
• Planned: Phase 1/2A studies with oral BAL101553
22
Acknowledgements