- Interim data from an
investigator-initiated study in first-line maintenance setting for
advanced pancreatic cancer suggest that Rubraca provides disease
control with no new safety signals in 19 evaluable
platinum-sensitive patients with germline BRCA1, germline or
somatic BRCA2, or germline PALB2 mutations
- Clovis is evaluating a potential
clinical and regulatory path forward for Rubraca in pancreatic
cancer
- Nonclinical studies of rucaparib and
lucitanib in multiple solid tumor types and Rubraca Trials in
Progress posters also presented at AACR 2019
Clovis Oncology, Inc. (NASDAQ: CLVS) today announced multiple
presentations at the 2019 American Association for Cancer Research
(AACR) Annual Meeting in Atlanta, March 29 – April 3, 2019. These
include today’s presentation of interim results from an
investigator-initiated Phase 2 trial of Rubraca® (rucaparib) in
platinum-sensitive patients with advanced pancreatic cancer. Early
data from the study are encouraging and suggest that first-line
maintenance therapy with Rubraca following induction with
platinum-based chemotherapy provides disease control with no new
safety signals among patients with a pathogenic mutation in BRCA1,
BRCA2 or PALB2. Between 5 to 8 percent of patients with pancreatic
cancer have a pathogenic mutation in BRCA1, BRCA2 or PALB2.
“PARP inhibitors have demonstrated activity in multiple cancers
that are associated with BRCA mutations,” said Kim A. Reiss Binder,
MD, Assistant Professor of Medicine in the Perelman School of
Medicine at the University of Pennsylvania and primary investigator
for the rucaparib study. “Given the seemingly intractable challenge
presented by pancreatic cancer, we are very pleased that early
results from this study support the mounting evidence suggesting
PARP inhibitors may have a beneficial role in this disease.”
The University of Pennsylvania-based study is an ongoing,
single-arm phase 2 trial investigating monotherapy Rubraca (600 mg
twice daily) in the first-line maintenance setting. The study will
enroll a total of 42 patients with advanced pancreatic cancer and a
pathogenic germline or somatic BRCA1, BRCA2 or PALB2 mutation,
whose cancer has not progressed following at least four months of
platinum-based chemotherapy. The primary endpoint of the trial is
progression-free survival (PFS) and responses are determined using
RECIST v1.1.
At the interim analysis, the median PFS in 19 evaluable patients
was 278 days or 9.1 months from the start of Rubraca therapy. At a
median potential follow-up of 244 days, median overall survival
(OS) had not been reached. According to the authors, of the 19
patients evaluated at the last data cutoff, one patient had a
complete response (CR) and six more patients had partial responses
(PR), including responses in patients with germline BRCA2 mutations
(n=4), germline PALB2 mutations (n=2) and somatic BRCA2 mutation
(n=1).
Eight of the 19 patients were on Rubraca for >6 months and
two patients remained on treatment for >1 year (13 months and 15
months). The disease control rate (defined as CR + PR + stable
disease) at 8 weeks follow-up was 89.5 percent.
Overall, Rubraca treatment in this study was well tolerated
without dose-limiting toxicities. The toxicities considered
possibly related to treatment occurring in >1 patient included
nausea (grade 1 or 2; 43.4%), dysgeusia (grade 1 or 2; 34.8%),
fatigue (grade 1 or 2; 26.1%), ALT increase (grade 1 or 2; 21.7%),
diarrhea (grade 1 or 2; 17.4%), vomiting (grade 1 or 2; 13%), AST
increase (grade 1 or 2; 13%) and anemia (grade 1 or 2; 8.6%). There
were no grade ≥3 events reported for these treatment related
toxicities.
“It is becoming clear that PARP inhibitors may offer a
much-needed new treatment option for the physicians and patients
who are facing the challenge of pancreatic cancer,” said Patrick J.
Mahaffy, President and CEO of Clovis Oncology. “Based on the
encouraging early findings from this investigator-initiated study,
as well as the findings from our own RUCAPANC trial of Rubraca in
pancreatic cancer, we are evaluating a potential clinical and
regulatory path forward for Rubraca in the treatment of pancreatic
cancer and hope to have more details later in 2019. In addition, at
AACR we are presenting nonclinical data that continue to expand our
understanding of both rucaparib and lucitanib to enhance our
development strategies.”
A poster titled “Comprehensive genomic profiling of >1000
plasma and tumor tissue samples from metastatic
castration-resistant prostate cancer (mCRPC) patients gives insight
into targeted treatment strategies” was presented Sunday. This
study highlighted the cancer genomics of tissue and plasma samples
screened for the TRITON2 study evaluating Rubraca in mCRPC.
Patients with deleterious alterations in DNA-damage repair (DDR)
genes were identified using both tissue and plasma-based assays,
and there was a high concordance between the alterations detected
with both assay types.
A poster titled “Enhancement of anti-PD-1 antitumor efficacy in
syngeneic preclinical models by the angiogenesis inhibitor
lucitanib” was presented Monday and shows that lucitanib combined
with an anti-PD-1 agent enhances the anti-tumor activity of either
single agent in multiple syngeneic animal models. The mechanism of
action is thought to be through both antiangiogenic effects and
immunomodulatory effects on dendritic cells and T cells. These data
provide preclinical support for a planned study of lucitanib in
combination with the anti-PD-1 inhibitor nivolumab in gynecologic
cancers, expected to initiate in the first half of 2019.
A poster titled “Intracranial evaluation of the in vivo
pharmacokinetics, brain distribution, and efficacy of rucaparib
in BRCA-mutant, triple-negative breast cancer” will be
presented later today. These data describe in vitro and in vivo
pharmacokinetic studies which suggest limited brain penetration of
multiple PARP inhibitors in mice with an intact blood-brain
barrier. However, antitumor activity was observed with Rubraca in a
BRCA1-mutant intracranial triple-negative breast cancer animal
model. The poster also includes a case report of a patient with
breast cancer associated with a germline BRCA2 mutation and CNS
involvement who had complete resolution of neurological symptoms
following Rubraca treatment. The data presented in the poster
provide insights into the complex pharmacokinetic and biological
parameters associated with CNS activity of PARP inhibitors.
Lastly, two Trials in Progress posters describing the trial
designs of the Clovis-sponsored ATHENA and ATLAS studies are also
being presented today. ATHENA is a Phase 3 study of Rubraca and
nivolumab following front-line platinum-based chemotherapy in
ovarian cancer. ATLAS is a Phase 2 study of Rubraca in patients
with locally advanced or metastatic urothelial carcinoma. Both
studies are currently enrolling patients.
Each of the Clovis-sponsored posters will be available online at
http://clovisoncology.com/pipeline/scientific-presentations/ as of
the time they are presented at the meeting.
About Pancreatic Cancer
Pancreatic cancer is the third leading cause of cancer death in
the United States (U.S.) though it is a relatively rare cancer as
the eleventh most common cancer. In 2019 in the U.S., an estimated
56,770 new cases will be diagnosed and 45,750 deaths due to the
disease will occur. Approximately 9% of pancreatic cancers harbor a
germline or somatic BRCA1 or BRCA2 (BRCA1/2) mutation and the
majority of patients are diagnosed with unresectable, locally
advanced or metastatic disease. Of the patients with resectable
disease, approximately 80% will relapse following surgery.
Currently, for all patients diagnosed with pancreatic cancer the
5-year survival rate is 8.5%.
About Rubraca (rucaparib)
Rucaparib is an oral, small molecule inhibitor of PARP1, PARP2
and PARP3 being developed in multiple tumor types, including
ovarian, metastatic castration-resistant prostate, and bladder
cancers, as monotherapy, and in combination with other anti-cancer
agents. Exploratory studies in other tumor types are also
underway.
Rubraca U.S. FDA Approved Indications
Rubraca is indicated as monotherapy for the maintenance
treatment of adult patients with recurrent epithelial ovarian,
fallopian tube, or primary peritoneal cancer who are in a complete
or partial response to platinum-based chemotherapy.
Rubraca is indicated as monotherapy for the treatment of adult
patients with deleterious BRCA mutations (germline and/or somatic)
associated epithelial ovarian, fallopian tube, or primary
peritoneal cancer who have been treated with two or more
chemotherapies and selected for therapy based on an FDA-approved
companion diagnostic for Rubraca.
Select Important Safety Information
Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML)
occur uncommonly in patients treated with Rubraca and are
potentially fatal adverse reactions. In approximately 1,100 treated
patients, MDS/AML occurred in 12 patients (1.1%), including those
in long-term follow-up. Of these, five occurred during treatment or
during the 28-day safety follow-up (0.5%). The duration of Rubraca
treatment prior to the diagnosis of MDS/AML ranged from 1 month to
approximately 28 months. The cases were typical of secondary
MDS/cancer therapy-related AML; in all cases, patients had received
previous platinum-containing regimens and/or other DNA-damaging
agents. Do not start Rubraca until patients have recovered from
hematological toxicity caused by previous chemotherapy (≤ Grade
1).
Monitor complete blood counts for cytopenia at baseline and
monthly thereafter for clinically significant changes during
treatment. For prolonged hematological toxicities (> 4 weeks),
interrupt Rubraca or reduce dose (see Dosage and Administration
[2.2] in full Prescribing Information) and monitor blood counts
weekly until recovery. If the levels have not recovered to Grade 1
or less after 4 weeks, or if MDS/AML is suspected, refer the
patient to a hematologist for further investigations, including
bone marrow analysis and blood sample cytogenetic analysis. If
MDS/AML is confirmed, discontinue Rubraca.
Based on its mechanism of action and findings from animal
studies, Rubraca can cause fetal harm when administered to a
pregnant woman. Apprise pregnant women of the potential risk to a
fetus. Advise females of reproductive potential to use
effective contraception during treatment and for 6 months following
the last dose of Rubraca.
Most common adverse reactions in ARIEL3 (≥ 20%; Grade 1–4) were
nausea (76%), fatigue/asthenia (73%), abdominal pain/distention
(46%), rash (43%), dysgeusia (40%), anemia (39%), AST/ALT elevation
(38%), constipation (37%), vomiting (37%), diarrhea (32%),
thrombocytopenia (29%), nasopharyngitis/upper respiratory tract
infection (29%), stomatitis (28%), decreased appetite (23%) and
neutropenia (20%).
Most common laboratory abnormalities in ARIEL3 (≥ 25%; Grade
1–4) were increase in creatinine (98%), decrease in hemoglobin
(88%), increase in cholesterol (84%), increase in alanine
aminotransferase (ALT) (73%), increase in aspartate
aminotransferase (AST) (61%), decrease in platelets (44%), decrease
in leukocytes (44%), decrease in neutrophils (38%), increase in
alkaline phosphatase (37%) and decrease in lymphocytes (29%).
Most common adverse reactions in Study 10 and ARIEL2 (≥ 20%;
Grade 1–4) were nausea (77%), asthenia/fatigue (77%), vomiting
(46%), anemia (44%), constipation (40%), dysgeusia (39%), decreased
appetite (39%), diarrhea (34%), abdominal pain (32%), dyspnea (21%)
and thrombocytopenia (21%).
Most common laboratory abnormalities in Study 10 and ARIEL2 (≥
35%; Grade 1–4) were increase in creatinine (92%), increase in
alanine aminotransferase (ALT) (74%), increase in aspartate
aminotransferase (AST) (73%), decrease in hemoglobin (67%),
decrease in lymphocytes (45%), increase in cholesterol (40%),
decrease in platelets (39%) and decrease in absolute neutrophil
count (35%).
Co-administration of Rubraca can increase the systemic exposure
of CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates, which may increase
the risk of toxicities of these drugs. Adjust dosage of CYP1A2,
CYP3A, CYP2C9, or CYP2C19 substrates, if clinically indicated. If
co-administration with warfarin (a CYP2C9 substrate) cannot be
avoided, consider increasing frequency of international normalized
ratio (INR) monitoring. Because of the potential for serious
adverse reactions in breast-fed children from Rubraca, advise
lactating women not to breastfeed during treatment with Rubraca and
for 2 weeks after the last dose. You may report side effects to the
FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may
also report side effects to Clovis Oncology, Inc. at
1-844-258-7662.
Click here for full Prescribing Information and additional
Important Safety Information.
Rubraca®▼ (rucaparib) EU Authorized Use and
Important Safety Information
Rucaparib is indicated as monotherapy for the maintenance
treatment of adult patients with platinum-sensitive relapsed
high-grade epithelial ovarian, fallopian tube, or primary
peritoneal cancer who are in response (complete or partial) to
platinum-based chemotherapy.
Rucaparib is indicated as monotherapy treatment of adult
patients with platinum sensitive, relapsed or progressive, BRCA
mutated (germline and/or somatic), high-grade epithelial ovarian,
fallopian tube, or primary peritoneal cancer, who have been treated
with two or more prior lines of platinum-based chemotherapy, and
who are unable to tolerate further platinum-based chemotherapy.
Summary warnings and precautions: Haematological
toxicity: Patients should not start Rubraca until they have
recovered from haematological toxicities caused by previous
chemotherapy (≤ CTCAE Grade 1). Complete blood count testing prior
to starting treatment with Rubraca and monthly thereafter is
advised. Rubraca should be interrupted or dose reduced and blood
counts monitored weekly until recovery for the management of low
blood counts. Myelodysplastic syndrome/acute myeloid leukaemia
(MDS/AML): If MDS/AML is suspected, the patient should be referred
to a haematologist for further investigation. If MDS/AML is
confirmed, Rubraca should be discontinued. Photosensitivity:
Patients should avoid spending time in direct sunlight as they may
burn more easily. When outdoors, patients should wear protective
clothing and sunscreen with SPF of 50 or greater. Gastrointestinal
toxicities: Low grade (CTCAE Grade 1 or 2) nausea and vomiting may
be managed with dose reduction or interruption. Additionally,
antiemetics may be considered for treatment or prophylaxis.
Click here to access the current Summary of Product
Characteristics. Healthcare professionals should report any
suspected adverse reactions via their national reporting
systems.
About Lucitanib
Lucitanib is an oral, potent inhibitor of the tyrosine kinase
activity of vascular endothelial growth factor receptors 1 through
3 (VEGFR1-3), platelet-derived growth factor receptors alpha and
beta (PDFGRα/β) and fibroblast growth factor receptors 1 through 3
(FGFR1-3).
Emerging clinical data support the combination of angiogenesis
inhibitors and immunotherapy to increase effectiveness in multiple
cancer indications. Angiogenic factors, such as vascular
endothelial growth factor (VEGF), are frequently up-regulated in
tumors and create an immunosuppressive tumor microenvironment. Use
of antiangiogenic drugs reverses this immunosuppression and can
augment response to immunotherapy.
Lucitanib is an unlicensed medical product.
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, with partners,
diagnostic tools intended to direct a compound in development to
the population that is most likely to benefit from its use. Clovis
Oncology is headquartered in Boulder, Colorado; please visit
www.clovisoncology.com for more information, including additional
office locations in the U.S. and Europe.
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. Examples of forward-looking
statements contained in this press release include, among others,
statements regarding our evaluation of Rubraca and lucitanib, a
candidate in development, in additional indications and tumor types
and potential for clinical and regulatory paths. Such
forward-looking statements involve substantial risks and
uncertainties that could cause our future results, performance or
achievements to differ significantly from that expressed or implied
by the forward-looking statements. Such risks and uncertainties
include, among others, the uncertainties inherent in our clinical
development programs for our drug candidates, the risk that
results of further trials may differ from initial or interim
results, nonclinical or preclinical studies, or post-hoc analyses,
as a result of many factors, including final results from a larger
patient population differing from initial or interim results from a
smaller patient population, and the uncertainties inherent in
actions by the FDA, the EMA or other regulatory authorities
regarding data required to support drug applications
and whether to accept or approve drug applications that may be
filed, as well as their decisions regarding drug labeling,
reimbursement and pricing. Clovis Oncology does not undertake to
update or revise any forward-looking statements. A further
description of risks and uncertainties can be found in Clovis
Oncology’s filings with the Securities and Exchange Commission,
including its Annual Report on Form 10-K and its reports on Form
10-Q and Form 8-K.
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version on businesswire.com: https://www.businesswire.com/news/home/20190402005328/en/
Clovis Investor Contacts:Anna Sussman,
303-625-5022asussman@clovisoncology.comorBreanna Burkart,
303-625-5023bburkart@clovisoncology.com
Clovis Media Contacts: U.S.Lisa Guiterman,
301-217-9353clovismedia@sambrown.comorChristy Curran,
615-414-8668clovismedia@sambrown.com
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