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Objective responses seen in BRCA-mutant ovarian, breast and
pancreatic cancer patients
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Disease control rate in BRCA-mutant ovarian cancer patients across
all doses of 100% and 63% at 12 weeks and 24 weeks, respectively
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Rucaparib well-tolerated at recommended Phase II dose of 600 mg BID
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Consistent therapeutic drug exposures observed with BID dosing
BOULDER, Colo.--(BUSINESS WIRE)--Sep. 29, 2013--
Clovis Oncology (NASDAQ:CLVS) today announced updated results from an
ongoing Phase I/II monotherapy study of rucaparib, the Company’s oral,
potent, small molecule poly (ADP-ribose) polymerase (PARP) inhibitor
being developed for the treatment of ovarian cancer. Data from the Phase
I dose-escalation portion of this Phase I/II study are being presented
today at a poster session during the European Cancer Congress 2013 in
Amsterdam.
"We’ve seen significant clinical activity with one complete response in
breast cancer and six partial responses in ovarian, breast and
pancreatic cancers to date, and a disease control rate in patients with
germline BRCA mutant ovarian (platinum-sensitive and platinum-resistant)
cancer of 100% and 63% at 12 and 24 weeks, respectively. I am pleased to
be participating in the Phase II and pivotal Phase III trials (ARIEL2
and ARIEL3) which aim to build on the clear activity of rucaparib in
BRCA-mutant ovarian cancer and prospectively identify and test other
genetic mutations associated with sensitivity to PARP inhibition in
ovarian cancer. This approach has the potential to broaden applicability
of PARP inhibitor treatment for ovarian cancer as well as other solid
tumors and hopefully benefit many patients,” said Dr. Rebecca
Kristeleit, Clinical Senior Lecturer and Consultant Medical Oncologist
UCLH and UCL Cancer Institute in London.
“These data demonstrate that rucaparib is both well-tolerated and
predictably absorbed, and provides meaningful clinical benefit to
certain ovarian cancer patients,” said Patrick J. Mahaffy, President and
CEO of Clovis Oncology. “Now that we have identified the recommended
Phase II dose, we plan to commence our late-stage development program in
platinum-sensitive ovarian cancer. This includes a now-open biomarker
study known as ARIEL2 (the Assessment of Rucaparib in Ovarian Cancer
Phase 2 Trial) which will refine the definition of patients beyond those
with BRCA mutations who may benefit from rucaparib. By the end of 2013
we expect to initiate a Phase III pivotal trial known as ARIEL3 in a
broad set of ovarian cancer patients with a stratified efficacy analysis
in genetically-defined groups, including somatic and germline BRCA
mutations as well as a population with mutations beyond BRCA, utilizing
insights from the ARIEL2 study.”
Today’s poster presentation includes data from the Phase I dose
escalation portion of the study, which is open to patients with any
solid tumor. Study objectives were typical for a Phase I trial,
including determining safety and tolerability, evaluating the
pharmacokinetic profile, identifying the maximum tolerated dose (MTD)
and recommended Phase II dose (RP2D) as well as the preliminary efficacy
signals in various solid tumors.
Fifty-three patients have been treated with rucaparib monotherapy in
this study as of September 2013, in once-daily (QD) and twice-daily
(BID) dosing cohorts, up to 500 mg QD and 840 mg BID. A dose of 600 mg
BID has been selected as the recommended Phase 2 dose based on maximum
exposure, manageable toxicity and activity. Rucaparib is well tolerated
up to 600 mg BID with minimal Grade 3 and no Grade 4 adverse events. No
patients have discontinued rucaparib due to a treatment-related adverse
event.
Patients have received a median of four previous anticancer regimens and
40 percent have received five or more previous therapies. Twenty-six
patients (50%) have breast tumors, 19 patients (37%) have
ovarian/peritoneal tumors and seven patients (13%) have other solid
tumors.
Key data from the study presented at the conference include the
following:
Evidence of Activity
To date, seven RECIST responses have been observed during the dose
escalation phase of the study (note: measurable disease and/or elevated
CA-125 was not required for study entry). In ovarian cancer patients
with a germline BRCA (gBRCA) mutation, two RECIST partial responses
(PRs) and one GCIC CA-125 response have been observed to date. Responses
have been observed in both platinum-sensitive and platinum-resistant
disease. In breast cancer patients with a germline BRCA mutation, one
RECIST complete response (CR) and three RECIST PRs have been observed.
In addition, a pancreatic cancer patient with a gBRCA2 mutation who
progressed rapidly on FOLFIRINOX therapy achieved a RECIST PR which is
ongoing at 25 weeks.
Overall, 100% (11/11) of ovarian cancer patients with gBRCA mutations
achieved disease control as defined by CR, PR, or stable disease (SD)>12
weeks and 63% (5/8) have achieved disease control as defined by CR, PR,
or SD >24 weeks – the three patients who progressed by week 24 were all
treated in dose cohorts of 300 mg QD or lower.
Safety and Tolerability
Safety data to date shows rucaparib to be well-tolerated, which is
important for a drug intended to be used in a maintenance setting.
Adverse events (AEs) were almost all low-grade and manageable. There
have been no grade 4 AEs reported to date, and no discontinuations due
to treatment-related adverse events. The most common adverse events
attributed to rucaparib therapy include nausea (29%), vomiting (21%) and
fatigue (23%). There was one dose-limiting toxicity (DLT) in a patient
in the 360 mg BID cohort who reported grade 3 nausea. Six patients (11%)
had a dose reduction and/or re-treatment delay, due to grade 3
thrombocytopenia (n=1), grade 3 anemia (n=1), grade 3 nausea (n=1),
grade 2 neutropenia (n=2), and grade 2 abdominal pain (n=1).
Myelosuppression is dose-related.
Pharmacokinetics
Oral rucaparib demonstrates attractive pharmacokinetic (PK) properties
as a potential oral cancer therapeutic, including plasma drug
concentrations maintained over a 24-hour period after BID dosing, which
is likely important for optimal activity. Intra- and inter-patient
variability was also low, which is advantageous for uniform flat dosing
strategies. This tight correlation between administered dose and plasma
exposure suggests that rucaparib dosing will lead to predictable results
across the ovarian cancer population. Predictable PK following oral
dosing may lead to low rates of over- and under-dosing, potentially
minimizing adverse events associated with high unpredictable exposures,
an important attribute for maintenance therapy. Greater than 85 percent
of ovarian cancer patients treated with rucaparib doses of 300 mg QD or
higher remain on study, with duration of benefit up to 60 weeks to date.
The poster, titled “A Phase I Dose Escalation and Pharmacokinetic Study
of Continuous Oral Rucaparib in Patients with Advanced Solid Tumors”, is
being presented on Sunday, September 29, 2013, 9:30am – 12:00pm CEST, in
Hall 4, Poster Board: P076 at Amsterdam RAI in Amsterdam. The poster
will also be available at http://www.clovisoncology.com/products-companion-diagnostics/scientific-presentations/.
About Rucaparib
Rucaparib is an oral, potent inhibitor of PARP1 and PARP2 in development
for the treatment of ovarian cancer. Rucaparib is currently in two
Company-sponsored Phase I clinical studies; one to determine the MTD of
oral rucaparib administered on a daily basis as monotherapy; and a
second trial to determine the MTD of oral rucaparib that can be combined
with intravenous platinum chemotherapy for the treatment of solid
tumors. Now that the optimal dose and schedule of 600 mg BID have been
established in the Phase I portion of the monotherapy study, the Company
intends to initiate a Phase II expansion cohort to assess efficacy in
gBRCA ovarian cancer patients. In addition, the Company has initiated
the ARIEL2 biomarker study in platinum-sensitive ovarian cancer
patients, and expects to initiate the ARIEL3 pivotal Phase III study in
platinum-sensitive ovarian cancer patients by the end of 2013.
About Clovis Oncology
Clovis Oncology, Inc. is a biopharmaceutical company focused on
acquiring, developing and commercializing innovative anti-cancer agents
in the U.S., Europe and additional international markets. Clovis
Oncology targets development programs at specific subsets of cancer
populations, and simultaneously develops diagnostic tools that direct a
compound in development to the population that is most likely to benefit
from its use. Clovis Oncology is headquartered in Boulder, Colorado, and
has additional offices in San Francisco, California and Cambridge, UK.
To the extent that statements contained in this press release are not
descriptions of historical facts regarding Clovis Oncology, they are
forward-looking statements reflecting the current beliefs and
expectations of management made pursuant to the safe harbor provisions
of the Private Securities Litigation Reform Act of 1995. Such
forward-looking statements involve substantial risks and uncertainties
that could cause our clinical development programs, future results,
performance or achievements to differ significantly from those expressed
or implied by the forward-looking statements. Such risks and
uncertainties include, among others, the uncertainties inherent in the
initiation of future clinical trials, availability of data from ongoing
clinical trials, expectations for regulatory approvals, and other
matters that could affect the availability or commercial potential of
our drug candidates. Clovis Oncology undertakes no obligation to update
or revise any forward-looking statements. For a further description of
the risks and uncertainties that could cause actual results to differ
from those expressed in these forward-looking statements, as well as
risks relating to the business of the company in general, see Clovis
Oncology’s Annual Report on Form 10-K for the year ended December 31,
2012 and its other reports filed with the Securities and Exchange
Commission.
Source: Clovis Oncology, Inc.
Clovis Oncology, Inc.
Anna Sussman, 303-625-5022
asussman@clovisoncology.com
or
Breanna
Burkart, 303-625-5023
bburkart@clovisoncology.com