Annual Meeting Proceedings Part 1 - American Society of Clinical ...

3048 General Poster Session (Board #13F), Mon, 8:00 AM-12:00 PM
Safety and efficacy results from two randomized expansions of a phase I
study of a tablet formulation of the PARP inhibitor, olaparib, in ovarian and
breast cancer patients with BRCA1/2 mutations. Presenting Author: L
Rhoda Molife, Royal Marsden Hospital and Institute of Cancer Research,
Surrey, United Kingdom
Background: We previously reported the comparative bioavailability of the
capsule (CAP) formulation of olaparib and the more convenient new tablet
(TAB) formulation (Molife et al ASCO 2010). We subsequently performed
two separate dose expansions (DE1 and DE2) to explore comparative safety
and efficacy of the TAB (NCT00777582). Methods: Patients with breast or
ovarian cancer and BRCA1/2 mutations, ECOG PS 0–2 and adequate organ
function were randomized to receive: DE1: 200 TAB or 400 CAP; DE2: 300
TAB, 400 TAB or 400 CAP (all mg BID). Endpoints included safety,
pharmacokinetics and exploratory analysis of efficacy (change in tumor size
at 8 weeks by RECIST 1.0). Groups were compared using analysis of
covariance, including baseline tumor size and treatment as covariates;
results are presented using least square (LS) means. Results: 24 patients
(ovarian n�15, breast n�9) entered DE1 and 53 patients (ovarian n�38,
breast n�15) entered DE2. Baseline characteristics including age, BRCA
mutation status and tumor histology were balanced. The table shows key
toxicity-related information and change in tumor size at 8 weeks by cohort.
Conclusions: These data suggest a dose-response effect for tolerability and,
possibly, efficacy with the new TAB between 200 and 400 mg BID. Further
studies will require dosing according to patient tolerability within this dose
range.
DE1 DE2
200 TAB 400 CAP 300 TAB 400 TAB 400 CAP
(n�13) (n�11) (n�18) (n�16) (n�18)
G3/4 AEs, n (%)
Nausea 0 0 0 2 (13%) 0
Fatigue 0 0 3 (17%) 1 (6%) 0
Diarrhea 0 0 2 (11%) 0 0
Anemia (Hb changes)
Other, n (%)
0 0 4 (22%) 4 (25%) 1 (6%)
Blood transfusions
Dose modifications, n (%)
0 0 5 (28%) 7 (44%) 2 (11%)
Dose reductions 2 (15%) 1 (9%) 4 (22%) 10 (63%) 3 (17%)
Drug discontinuations due to AEs
Change in tumor size, 8 weeks
0 0 0 0 0
LS, mean (%) 4.5 -12.8 -6.8 -28.6 -27.8
Difference 17.3 21.0 -0.8
95% CI -11.8, 46.3 1.3, 40.7 -20.8, 19.3
3050 General Poster Session (Board #13H), Mon, 8:00 AM-12:00 PM
Developing rational drug combination strategies for PARP inhibitors.
Presenting Author: Farah Rehman, The Institute of Cancer Research,
London, United Kingdom
Background: The recent clinical development of Poly (ADP-ribose) polymerase
(PARP) inhibitors has provided formal proof-of-concept that synthetic
lethal approaches can be used to treat cancer. The promise of PARP
inhibitors in BRCA mutant tumours is apparent but questions regarding
their wider clinical use remain. To date, a number of clinical trials have
been designed using PARP inhibitors as single agents as well as in
combination with current standards of care. However, there is a paucity of
pre-clinical information about PARP inhibitor/drug combinations and
empirical clinical trials of standard of care plus PARP inhibitors may not
represent the most effective approach to dissect this. We aim to identify
effective drug combination strategies that could be used clinically in
selected patient groups. Methods: Using a combination of high and medium
throughput techniques and established methodologies for determining
synergy, additivity and antagonism, we have characterised the effects of
combining PARP inhibitors with a diverse panel of over 3,000 compounds
in a range of tumour cell models including isogenic matched cell line pairs
to determine the impact of genetic background on drug combination
efficacy. We have integrated this data with functional profiling data to
identify genetic backgrounds where these combinations may be most
effective. Results: Results to date suggest promising combinations of PARP
inhibitors with temozolomide, CHK1 inhibitors, ATM inhibitors and other
agents. Some of these combinations show specificity for genetic backgrounds
such as PTEN mutations. Conclusions: Screening of drug libraries
has identified promising PARP inhibitor drug combinations and demonstrates
how some drug combinations show specificity in particular genetic
backgrounds. This raises the possibility of widening the therapeutic index
in patients with these genetic backgrounds and treating a wider group of
patients with PARP inhibitors.
Developmental Therapeutics—Experimental Therapeutics
185s
3049 General Poster Session (Board #13G), Mon, 8:00 AM-12:00 PM
A phase I study of veliparib (ABT-888) in combination with carboplatin and
paclitaxel in advanced solid malignancies. Presenting Author: Leonard
Joseph Appleman, University of Pittsburgh Cancer Institute, Pittsburgh, PA
Background: Veliparib (ABT-888, NSC 737664) is an orally available
inhibitor of poly(ADP-ribose) polymerase (PARP)-1 and -2: enzymes that
recruit base excision repair machinery to single-stranded DNA breaks.
Expression of PARP-1 may be increased in cancer cells and confer
resistance to DNA-damaging agents. The objectives of this phase I study
included determination of the recommended phase 2 dose (RP2D),
maximum tolerated dose (MTD), dose limiting toxicity (DLT) and pharmacokinetics
(PK) of veliparib in combination with paclitaxel (P) and carboplatin
(C). Methods: Eligibility criteria included advanced solid tumors, � 3 prior
chemotherapy regimens for advanced disease, ECOG performance status
0-2. Veliparib was given PO BID on days 1-7 of each 21 day cycle, and P
and C were administered on day 3. In dose levels 1-7, veliparib was not
given during cycle 1 to serve as intra-patient control for toxicity and PK
assessment, and DLT was evaluated during cycle 2. A standard “3�3”
dose escalation was utilized starting at veliparib 20 mg BID, P 150 mg/m2,
C AUC 5. Plasma concentrations of veliparib, P and C were determined by
LC-MS/MS and AAS during cycle 1 and 2. Results: To date, 68 patients
have been enrolled. Tumor types included lung (15), breast (14), melanoma
(10), squamous cell of head/neck (7), and urothelial (5). Toxicities
observed were expected with C plus P chemotherapy, including neutropenia,
thrombocytopenia, peripheral neuropathy. DLTs were seen in 2 out of 7
evaluable patients at the maximum administered dose: veliparib 120 mg
BID, P 200 mg/m2 , C AUC 6, (febrile neutropenia, hyponatremia).
Veliparib 80 mg, P 200 mg/m2 , C AUC 6 was well tolerated with 1 out of 9
DLT (febrile neutropenia). Median number of cycles was 5 (1-17). Partial
response was seen in 11 (Lung-2, breast-2, melanoma-2, urothelial-2,
head and neck, gastric, unknown primary) and complete response in 1
patient with breast cancer and 1 patient with urothelial cancer. Stable
disease was observed in 35 patients. Veliparib did not affect the PK
disposition of P or C. Conclusions: Veliparib in combination with P and C
was well-tolerated with a safety profile similar to P and C alone. Promising
anti-tumor activity was observed in several tumor types.
3051 General Poster Session (Board #14A), Mon, 8:00 AM-12:00 PM
Phase I study to determine the bioavailability and tolerability of a tablet
formulation of the PARP inhibitor olaparib in patients with advanced solid
tumors: Dose-escalation phase. Presenting Author: Avinash Gupta, Oxford
University Hospitals NHS Trust, Oxford, United Kingdom
Background: We previously reported the comparative bioavailability of the
olaparib tablet (TAB) up to 200 mg BID, with the initial capsule formulation;
gmean AUC0–Tfollowing 200 mg BID TAB was ~20% lower than 400
mg BID capsule (CAP; Molife et al ASCO 2010). Olaparib 200 mg BID TAB
had an acceptable tolerability profile suggesting further dose escalation
might be justified. Methods: Study NCT00777582 was amended to include
a dose-escalation phase, to define the maximum tolerated dose (MTD) and
safety profile of the TAB, and 2 expansion phases to compare safety and
efficacy of TAB doses vs 400 mg BID CAP. Expansion phase data are
reported separately. Here, we report preliminary data from the doseescalation
phase where patients (pts) with advanced solid tumors, ECOG
PS 0–2 and adequate organ function were assigned to treatment with
increasing olaparib BID TAB doses in 28-day continuous dosing cycles.
Pharmacokinetic (PK) sampling was performed on days 1, 8, 15, 29, 57.
Results: 30 pts (M:F, 3:27; median age 54 yrs [range 19–70]) were
enrolled in the dose-escalation phase and received treatment at 5 dose
levels: 250, 300, 350, 400 and 450 mg (each dose level, n�6). Overall,
the most common AEs were nausea (80%), fatigue (73%) and diarrhea
(36%). The majority of AEs were mild to moderate (CTC grade [G] 1/2).
Hematologic toxicity in terms of, mostly mild, anemia, neutropenia and
thrombocytopenia, appeared to increase at doses of 300 mg BID or higher.
Two pts had dose-limiting toxicities at 450 mg (G3 thrombocytopenia and
G3 anemia); the TAB MTD was 400 mg BID. Exposure increased proportionally
with increasing dose: mean exposure after 400 mg BID was double that
following the previously reported 200 mg BID dose. Following 300 and 400
mg doses, gmean Cmax ss, AUC0–Tand Cmin ss matched or exceeded the 400
mg BID CAP dose. Conclusions: The MTD of olaparib TAB was 400 mg BID.
Based on PK analysis, the 300 and 400 mg BID doses were selected for
evaluation in the MTD expansion phase to further define safety and
preliminary efficacy.
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