denotes an abstract that is clinically relevant.
denotes that this is a recommended PHD Trainee Session.
denotes that this is a ticketed session.Program: Oral and Poster Abstracts
Session: 616. Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation: Poster III
Background: Essential to cancer cell signaling, the growth receptor bound protein-2 (Grb-2) is evolutionarily conserved and utilized by oncogenic tyrosine kinases including Bcr-Abl to activate Ras, ERK, and AKT. BP-100-1.01 is a neutrally-charged, liposome-incorporated antisense designed to inhibit Grb-2 expression.
Aim: To define the safety, maximum tolerated dose (MTD), optimal biologically active dose, pharmacokinetics and anti-leukemia activity of BP-100-1.01 in patients (pts) with hematologic malignancies.
Methods: This is a standard 3+3 phase I dose-finding study in pts with relapsed or refractory acute myeloid leukemia (AML), chronic myeloid leukemia in blast phase (CML-BP), acute lymphoblastic leukemia (ALL) and myelodysplastic syndrome (MDS). The starting dose was 5 mg/m2 twice weekly, IV over 2-3 hours for 28 days. Dose escalation proceeded through 5, 10, 20, 40, 60, and 90 mg/m2. Upon completion of single agent phase 1, combination of cytarabine 20 mg SubQ BID x 10 days + 60 mg/m2 of BP-100-1.01 was studied (Cohort 1B). Flow cytometric analysis was performed on peripheral blood samples from cohorts 3, 4, 5, 6 and 1B collected at baseline, on day 15 and at end-of-treatment (EOT). Fluorescent-labeled antibodies specific for Grb-2 or phosphorylated Erk (pErk) were utilized to determine Grb-2 protein levels and pErk levels in CD33-expressing cells.
Results: A total of 33 pts were included (13 in Cohort 1, 6 in Cohort 2, 3 each in Cohorts 3, 4, 5, and 4 in cohort 6). One patient has been treated in cohort 1B. The median age was 64 yrs (range, 32-89) and diagnoses were AML (n=24), CML-BP (n=5) and MDS (n=4). The median number of prior therapies was 4 (range, 1- 8). Of 33 pts, 21 were evaluable and 11 failed completion of a full 28-Day cycle due to disease progression (with no toxicity) and were replaced, per protocol. Only one pt (treated at 5 mg/m2) experienced dose limiting toxicity (DLT), grade 3 mucositis and hand-foot syndrome, while receiving concurrent hydroxyurea for proliferative CML-BP. The patient had a previous history of hydroxyurea-induced mucositis. Being the first patient to receive BP-100-1.01, these toxicities were considered possibly related to BP-100-1.01. The cohort was expanded to a total of 6 pts. No other DLTs have been noted in any pt. Among 21 evaluable pts, 11 experienced at least a 50% reduction in peripheral or bone marrow blasts from baseline. Additionally 2 pts with improvement in leukemia cutis lesions received 1 cycle each. Furthermore, 6 pts demonstrated transient improvement (n=3) and/or stable disease (n=3). Among the 21 evaluable pts, a median of 1 cycle was administered (1-5): Four pts received 2 cycles, 3 pts received 5 cycles, and all others received 1 cycle. Notably one pt (treated at 5 mg/m2) with CML-BP showed a significant reduction in blasts from 81% to 5%. Due to leptomeningeal disease progression therapy was discontinued before a full cycle. The 1st patient treated in cohort 1B achieved CR after 1 cycle. The patient did not experience any DLTs, but came off study due to failure to thrive in the context of dementia.
The levels of Grb-2 and pErk proteins were indicated by their respective median fluorescent signals and are shown in the table. Median fluorescent signals of Grb-2 and pErk on days 15 and EOT were compared to baseline. On day 15 Grb-2 levels decreased by >25% in 7 out of 12 samples tested, and pErk levels by >25% in 6 out of 12 samples. The average decrease in Grb-2 levels was 61% (range: 47 to 85%) and in pErk levels 52% (range: 28 to 82%). On the last measured sample (EOT or day 22), BP-100-1.01 decreased >25% Grb-2 levels in 11 out of 13 samples, and >25% pErk levels in 7 out of 13 samples. The average decrease in Grb-2 levels was 49% (range: 28 to 91%) and in pErk levels was 52% (range: 27 to 91%).
Patient Number |
Grb-2 decrease (Day 15) |
pErk decrease (Day 15) |
Grb-2 decrease (Day 22 or EOT) |
pErk decrease (Day 22 or EOT) |
022 |
0 |
0 |
57 |
0 |
023 |
0 |
3 |
28 |
45 |
024 |
56 |
28 |
47 |
35 |
025 |
63 |
82 |
54 |
91 |
026 |
47 |
0 |
0 |
0 |
027 |
NS |
NS |
34 |
27 |
028 |
0 |
0 |
30 |
54 |
029 |
57 |
51 |
65a |
0a |
030 |
54 |
55 |
43 |
47 |
031 |
0 |
0 |
0 |
0 |
032 |
85 |
54 |
91 |
63 |
033 |
6 |
13 |
53 |
2 |
034 |
63 |
42 |
40 |
0 |
NS = no sample collected aFewer cells were used in the analysis of this sample than other samples, because this sample had less cells than other samples
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Conclusions: BP-100-1.01, at dose range 5 mg/m2 to 90 mg/m2 is well tolerated with no MTD yet identified. There is suggestion of Grb-2 target protein down-regulation, and possible anti-leukemia activity.
Disclosures: Konopleva: Novartis: Research Funding ; AbbVie: Research Funding ; Stemline: Research Funding ; Calithera: Research Funding ; Threshold: Research Funding . Tari: Bopath Holdings: Employment . Cortes: BerGenBio AS: Research Funding ; Teva: Research Funding ; Novartis: Consultancy , Research Funding ; Pfizer: Consultancy , Research Funding ; Ariad: Consultancy , Research Funding ; BMS: Consultancy , Research Funding ; Astellas: Consultancy , Research Funding ; Ambit: Consultancy , Research Funding ; Arog: Research Funding ; Celator: Research Funding ; Jenssen: Consultancy .
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