- Initial data from the Phase 1b part of the LIO-1 trial of
lucitanib combined with Opdivo® (nivolumab) in advanced metastatic
solid tumors identify a recommended Phase 2 dose and show promising
signs of antitumor activity
- The first presentation of preclinical data for FAP-2286, a
novel peptide-targeted radionuclide therapy (PTRT), show the
compound potently and selectively binds fibroblast activation
protein (FAP); compelling anti-tumor activity was observed in
FAP-expressing tumor models
- New data analyses from pivotal Rubraca® (rucaparib) studies
ARIEL3 and TRITON2 further characterize its safety profile in
recurrent ovarian cancer and metastatic castration-resistant
prostate cancer (mCRPC), respectively
- Encouraging initial data from the SEASTAR study evaluating
Rubraca in combination
Clovis Oncology, Inc. (NASDAQ: CLVS) today announced the data
being presented as e-posters at the European Society for Medical
Oncology (ESMO) Virtual Congress 2020. These include initial data
from the Phase 1b part of the LIO-1 study of lucitanib in
combination with Opdivo, new analyses of data from the pivotal
Rubraca ARIEL3 and TRITON2 studies, initial data from the Phase 1b
part of the SEASTAR study arm of Rubraca with Trodelvy™
(sacituzumab govitecan-hziy), and the first presentation of
preclinical data for FAP-2286 Clovis’ novel peptide-targeted
radionuclide therapy.
“We are very pleased to present these encouraging initial
datasets for our pipeline compounds lucitanib and FAP-2286 today,
as well as data further characterizing and confirming the
established safety profile of Rubraca in advanced ovarian and
prostate cancers, which we believe provides additional, valuable
information to physicians and their patients,” said Patrick J.
Mahaffy, President and CEO of Clovis Oncology. “We are enthusiastic
about the potential of our clinical development programs for each
of our three compounds and remain committed to exploring the full
depth and breadth of our pipeline to transform the cancer treatment
landscape and hopefully improve outcomes for patients.”
Data presented today from the Phase 1b part of the Phase 1b/2
LIO-1 study in patients with an advanced solid tumor (n=17) have
identified the recommended starting Phase 2 dose of oral lucitanib
to be used in combination with Opdivo and have shown promising
signs of antitumor activity. The recommended oral starting dose of
lucitanib was established as 6 mg once daily, to be given in
combination with Opdivo at a fixed dose of 480 mg intravenously
(IV) once every 28 days. Across three dose levels studied (6 mg, 8
mg and 10 mg) of oral lucitanib in combination with intravenous
(IV) Opdivo at (480 mg once every 28 days), only one dose-limiting
toxicity of Grade 3 proteinuria was observed among 17 patients, and
there were no apparent differences in treatment-emergent adverse
event (TEAE) frequencies between dose levels. In this small patient
population, TEAEs were consistent with those expected for lucitanib
and Opdivo. Grade 3 TEAEs included hypertension (n=4), diarrhea
(n=1), and proteinuria (n=1); treatment-emergent hypertension was
otherwise grade 1 or 2 (n=4), and readily managed with close
monitoring and early hypertensive therapy. No grade ≥4 adverse
events were reported. Given lucitanib’s relatively large
inter-patient pharmacokinetic variability, a safety-based
dose-titration approach is being used for the Phase 2 part of the
study to optimize lucitanib efficacy as well as safety and
tolerability. Among the 17 patients treated, 15 were evaluable for
RECIST response as of the efficacy cut-off date: these include one
patient with a confirmed complete response, one patient with a
confirmed partial response, 10 patients have had a best response of
stable disease and three patients had progressive disease. As of
August 11, 2020, seven of the 17 patients remained on study,
including the two responders and five of the patients with stable
disease.
“We have completed enrollment in the Phase 1b part of the LIO-1
trial, and have identified a dose of lucitanib to take into Phase 2
combined with nivolumab. The combination showed promising signs of
activity in unselected solid tumors in patients with very advanced
disease, including one patient with a confirmed complete response,”
said Dr. Erika Hamilton, Director of the Breast and Gynecologic
Research Program, Sarah Cannon Research Institute at Tennessee
Oncology. “We were also encouraged by the initial safety profile,
in particular as it relates to constitutional side effects, and
hope to build on that with our dose-titration approach in the
ongoing Phase 2 part of the LIO-1 study. This will provide greater
understanding of what this combination may offer for the treatment
of patients with gynecological cancers.”
In addition to data from the Phase 1b part of the LIO-1 study, a
Trials in Progress (TiP) poster describing the study design of the
Phase 2 part of LIO-1 was presented. The Phase 2 part of the study
is currently enrolling patients to evaluate the efficacy and safety
of the lucitanib and Opdivo combination in patients with advanced
gynecological solid tumors, including ovarian, endometrial and
cervical cancers. As described in the e-poster, a safety-based
dose-titration approach is being used for lucitanib dosing to
manage tolerability and maintain dose intensity.
Investigators also presented today new safety data analyses from
the pivotal Rubraca studies ARIEL3 and pharmacokinetic (PK)
analyses of TRITON2, providing additional information to healthcare
professionals that can help support their ovarian and prostate
cancer patients being treated with Rubraca.
The ARIEL3 data presented in an e-poster reinforce the overall
safety profile of Rubraca as a maintenance treatment in patients
with recurrent ovarian cancer. After two years of additional follow
up for those patients who continued on treatment in the study, the
safety profile remains consistent with previous reports, with no
new safety signals identified. As of the current safety data cutoff
(December 31, 2019), 33 of 372 and 1 of 189 patients in the safety
population were still receiving Rubraca or placebo, respectively.
Median treatment duration was 8.3 months in the Rubraca arm and 5.5
months in the placebo arm. Prevalence of any-grade nausea declined
progressively over the 24-month evaluation period, and prevalence
of any-grade anemia/decreased hemoglobin peaked at month 4,
decreasing to a plateau after month 8. The first onset of
frequently reported TEAEs generally occurred early in treatment
(≤45 days). The median duration of the first event of frequently
reported TEAEs was generally <60 days.
Population pharmacokinetic (PK) analyses of 199 men with mCRPC
receiving Rubraca in the TRITON2 study suggest there is no
difference in Rubraca PK in men with mCRPC and women with ovarian
cancer based on a comparison to a previously-developed model that
used data from 454 women with ovarian cancer treated with Rubraca.
The data in men with mCRPC show that differences among patients in
the amount of Rubraca in the blood after administration of Rubraca
at a dose of 600 mg twice daily did not appear to impact the
efficacy of treatment. Also, a higher maximum concentration of
Rubraca in the blood was not associated with increased rates of
most safety endpoints analyzed, including hematologic adverse
events. These PK data and exposure and safety/efficacy correlations
using data from the TRITON2 study support the use of Rubraca in
eligible mCRPC patients with a starting dose of 600 mg twice daily.
TRITON2 served as the pivotal data supporting the May 2020 FDA
approval of Rubraca as the first PARP inhibitor for patients with
advanced mCRPC associated with a BRCA mutation.
Investigators also presented in an e-poster initial data from
the arm of the Phase 1b/2 SEASTAR study evaluating Rubraca in
combination with Trodelvy in patients with advanced solid tumors
(n=6). Data from the Phase 1b part of the study suggest encouraging
initial antitumor activity for the novel combination, including
patients with prior PARP inhibitor exposure and without a
deleterious homologous recombination repair gene mutation. Despite
early toxicities, including dose-limiting neutropenia in two of the
three patients in the higher dose cohort, all six patients
continued treatment for at least 12 weeks, with side effects
effectively managed with dose modification and/or growth factor
support. One patient remained on treatment as of the August 11,
2020 data cut-off date. All patients had a best response of stable
disease or better, including three patients with a confirmed
partial response (all three had been previously treated with a PARP
inhibitor).
And finally, the first data from a preclinical evaluation of
FAP-2286, Clovis’ novel peptide-targeted radionuclide therapy to
fibroblast activation protein (FAP) were presented in an e-poster.
The data show that FAP-2286 potently and selectively binds FAP. FAP
is highly expressed in cancer-associated fibroblasts (CAFs) present
in the tumor microenvironment of most epithelial cancers and, in
some cancers, its expression has also been observed in the tumor
cells. Compelling anti-tumor activity was observed with
177Lu-FAP-2286 (Lutetium-177 conjugated to FAP-2286 for therapeutic
use) in FAP-expressing tumor models. Clovis Oncology plans to
submit two Investigational New Drug (IND) applications in late 2020
for use of this novel radionuclide therapy as an imaging and
treatment agent, respectively, and the Company has planned clinical
studies in a broad spectrum of FAP-positive cancers.
Each of Clovis Oncology’s e-posters described are available
online at
www.clovisoncology.com/pipeline/scientific-presentations.
About Rubraca (rucaparib)
Rucaparib is an oral, small molecule inhibitor of PARP1, PARP2
and PARP3 being developed in multiple tumor types, including
ovarian and metastatic castration-resistant prostate cancers, as
monotherapy, and in combination with other anti-cancer agents.
Exploratory studies in other tumor types are also underway.
Rubraca is an unlicensed medical product outside of the U.S. and
Europe
Rubraca (rucaparib) European Union (EU) authorized use and
Important Safety Information
Rubraca 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.
Rubraca 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 ≥2
prior lines of platinum-based chemotherapy, and who are unable to
tolerate further platinum-based chemotherapy.
Efficacy of Rubraca as treatment for relapsed or progressive
epithelial ovarian cancer (EOC), fallopian tube cancer (FTC), or
primary peritoneal cancer (PPC) has not been investigated in
patients who have received prior treatment with a PARP inhibitor.
Therefore, use in this patient population is not recommended.
Summary warnings and precautions:
Hematological toxicity
During treatment with Rubraca, events of myelosuppression
(anemia, neutropenia, thrombocytopenia) may be observed and are
typically first observed after 8–10 weeks of treatment with
Rubraca. These reactions are manageable with routine medical
treatment and/or dose adjustment for more severe cases. Complete
blood count testing prior to starting treatment with Rubraca, and
monthly thereafter, is advised. Patients should not start Rubraca
treatment until they have recovered from hematological toxicities
caused by previous chemotherapy (CTCAE grade ≥1).
Supportive care and institutional guidelines should be
implemented for the management of low blood counts for the
treatment of anemia and neutropenia. Rubraca should be interrupted
or dose reduced according to Table 1 (see Posology and Method of
Administration [4.2] of the Summary of Product Characteristics
[SPC]) and blood counts monitored weekly until recovery. If the
levels have not recovered to CTCAE grade 1 or better after 4 weeks,
the patient should be referred to a hematologist for further
investigations.
MDS/AML
MDS/AML, including cases with fatal outcome, have been reported
in patients who received Rubraca. The duration of therapy with
Rubraca in patients who developed MDS/AML varied from less than 1
month to approximately 28 months.
If MDS/AML is suspected, the patient should be referred to a
hematologist for further investigations, including bone marrow
analysis and blood sampling for cytogenetics. If, following
investigation for prolonged hematological toxicity, MDS/AML is
confirmed, Rubraca should be discontinued.
Photosensitivity
Photosensitivity has been observed in patients treated with
Rubraca. Patients should avoid spending time in direct sunlight
because they may burn more easily during Rubraca treatment; when
outdoors, patients should wear a hat and protective clothing, and
use sunscreen and lip balm with sun protection factor of 50 or
greater.
Gastrointestinal toxicities
Gastrointestinal toxicities (nausea and vomiting) are frequently
reported with Rubraca, and are generally low grade (CTCAE grade 1
or 2), and may be managed with dose reduction (refer to Posology
and Method of Administration [4.2], Table 1 of the SPC) or
interruption. Antiemetics, such as 5-HT3 antagonists,
dexamethasone, aprepitant and fosaprepitant, can be used as
treatment for nausea/vomiting and may also be considered for
prophylactic (i.e. preventative) use prior to starting Rubraca. It
is important to proactively manage these events to avoid prolonged
or more severe events of nausea/vomiting which have the potential
to lead to complications such as dehydration or
hospitalization.
Embryofetal toxicity
Rubraca can cause fetal harm when administered to a pregnant
woman based on its mechanism of action and findings from animal
studies. In an animal reproduction study, administration of Rubraca
to pregnant rats during the period of organogenesis resulted in
embryo-fetal toxicity at exposures below those in patients
receiving the recommended human dose of 600 mg twice daily (see
Preclinical Safety Data [5.3] of the SPC).
Pregnancy/contraception
Pregnant women should be informed of the potential risk to a
fetus. Women of reproductive potential should be advised to use
effective contraception during treatment and for 6 months following
the last dose of Rubraca (see section 4.6 of the SPC). A pregnancy
test before initiating treatment is recommended in women of
reproductive potential.
Click here to access the current SPC. Healthcare professionals
should report any suspected adverse reactions via their national
reporting systems.
Rubraca U.S. FDA Approved Indications
Ovarian Cancer
Rubraca is indicated for the maintenance treatment of adult
women 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 for the treatment of adult women with a
deleterious BRCA mutation (germline and/or somatic)-associated
epithelial ovarian, fallopian tube, or primary peritoneal cancer
who have been treated with two or more chemotherapies. Select
patients for therapy based on an FDA-approved companion diagnostic
for Rubraca.
Prostate Cancer
Rubraca is indicated for the treatment of adult patients with a
deleterious BRCA mutation (germline and/or somatic)-associated
metastatic castration-resistant prostate cancer (mCRPC) who have
been treated with androgen receptor-directed therapy and a
taxane-based chemotherapy. This indication is approved under
accelerated approval based on objective response rate and duration
of response. Continued approval for this indication may be
contingent upon verification and description of clinical benefit in
confirmatory trials.
Select Important Safety Information
Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML)
occur in patients treated with Rubraca, and are potentially fatal
adverse reactions. In 1146 treated patients, MDS/AML occurred in 20
patients (1.7%), including those in long term follow-up. Of these,
8 occurred during treatment or during the 28 day safety follow-up
(0.7%). The duration of Rubraca treatment prior to the diagnosis of
MDS/AML ranged from 1 month to approximately 53 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 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 for cytogenetics. 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. For males on Rubraca treatment who have female
partners of reproductive potential or who are pregnant, effective
contraception should be used during treatment and for 3 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 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%).
Co-administration of rucaparib 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.
Please click here for full
Prescribing Information for
Rubraca.
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 may reverse this
immunosuppression and augment response to immunotherapy.
Lucitanib is an unlicensed medical product.
About FAP-2286
FAP-2286 is a preclinical candidate discovered by 3B
Pharmaceuticals under investigation as a peptide-targeted
radionuclide therapy (PTRT) and imaging agent targeting fibroblast
activation protein alpha (FAP). FAP is highly expressed in many
epithelial cancers, including more than 90 percent of breast, lung,
colorectal and pancreatic carcinomas. Clovis Oncology is planning
to submit an investigational new drug application (IND) for
FAP-2286 in the second half of 2020 and conduct the global clinical
trials. Clovis Oncology holds U.S. and global rights, excluding
Europe.
FAP-2286 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, for
those indications that require them, 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, with additional office locations in the U.S. and
Europe. Please visit www.clovisoncology.com for more
information.
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 expectations for submission of regulatory
filings, the timing and pace of commencement of and enrollment in
our clinical trials, including those being planned or conducted in
collaboration with partners, the potential results of such clinical
trials, our expectations regarding the suitability of each of
Rubraca, lucitanib and FAP-2286 for, and our plans to develop each
of Rubraca, lucitanib and FAP-2286 in, additional indications and
tumor types, and our expectations regarding the outcomes of early
studies or trials supporting further development, both non-clinical
and clinical. 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 and
those of our partners, whether future study results will be
consistent with study findings to date, the timing of availability
of data from our clinical trials and the initiation, enrollment,
timing and results of our planned clinical trials and the
corresponding development pathways, effectiveness and suitability
of diagnostic tests, the risk that final results of ongoing trials
may differ from initial or interim results as a result of factors
such as final results from a larger patient population may be
different from initial or interim results from a smaller patient
population, the risk that additional pre-clinical or clinical
studies may not support further development in certain additional
indications or tumor types, and actions by the FDA, the EMA or
other regulatory authorities regarding data required to support
drug applications and whether to approve drug applications. 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.
View source
version on businesswire.com: https://www.businesswire.com/news/home/20200917005247/en/
Clovis Investor Contacts: Anna Sussman, 303.625.5022
asussman@clovisoncology.com or Breanna Burkart, 303.625.5023
bburkart@clovisoncology.com
Clovis Media Contacts: U.S. Lisa Guiterman,
301.217.9353 clovismedia@sambrown.com
Europe Jake Davis, +44 (0) 20.3946.3538
Jake.Davis@publicisresolute.com
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