Partial Responses Observed in Patients With Heavily Pretreated Breast, Ovarian and Pancreatic Cancers Carrying BRCA Mutations
BERKELEY HEIGHTS, N.J., June 4, 2012 (GLOBE NEWSWIRE) -- Cyclacel Pharmaceuticals, Inc. (Nasdaq:CYCC) (Nasdaq:CYCCP) (Cyclacel or the Company), today announced new data from an open label, single arm, Phase 1 escalation trial of the Company's two product candidates, sapacitabine, a nucleoside analogue, and seliciclib, a CDK inhibitor, as an orally-administered sequential treatment regimen in heavily-pretreated patients with advanced solid tumors. Data were presented as a poster during the 2012 American Society of Clinical Oncology (ASCO) Annual Meeting being held June 1-5, 2012, in Chicago, Illinois.
"We are encouraged by the anti-tumor activity against advanced solid tumors with the sequential administration of sapacitabine and seliciclib," said Geoffrey Shapiro, M.D., Director, Early Drug Development Center, Dana-Farber Cancer Institute and Associate Professor, Department of Medicine, Harvard Medical School. "The partial responses in BRCA-mutation carrier patients with breast, pancreatic and ovarian cancers may be directly related to the mechanism of action of the oral investigational agents, sapacitabine and seliciclib, and their ability to interfere with DNA repair of cancer cells. The data warrant further investigation of the sequential administration of sapacitabine and seliciclib in advanced solid tumor patients that are BRCA-mutation carriers. BRCA status could be a potential biomarker for identifying responders across multiple solid tumor types."
Results
To date 34 heavily-pretreated patients with advanced solid
tumors have been treated with escalating doses. At ASCO, the
maximum tolerated dose
(MTD) for sequential administration of sapacitabine and seliciclib
was reported as sapacitabine 50 mg twice daily followed by
seliciclib 1200 mg twice daily. Pharmacodynamic effects of
sapacitabine and seliciclib were observed in skin biopsies showing
a 2.3-fold increase in H2AX staining post-sapacitabine (n=16;
p=0.007) and a further 0.58-fold increase post-seliciclib (n=12;
p=0.069).
Among 19 patients treated at the MTD, 3 partial responses (PR)
occurred in patients with breast, ovarian and pancreatic cancer and
1 stable disease in a patient with ovarian cancer. Thirteen out of
the 19 patients are BRCA-mutation carriers, of which 7 were poly
ADP-ribose polymerase (PARP)-inhibitor naive and 6 had prior PARP
inhibitor treatment. All four responding patients were PARP
inhibitor naive BRCA-mutation carriers. Stable disease was achieved
in 6 additional patients treated with the other dosing schedules.
The number of treatment cycles administered ranges from 2 to over
15 cycles. The breast cancer patient who achieved PR remains on
study with over 15 cycles and both ovarian cancer patients remain
on study with over 2 and
12 cycles respectively.
Study Design
In the open label Phase 1, single-arm dose escalation study of
sapacitabine, an orally-available nucleoside analogue, and
seliciclib, an orally-available CDK inhibitor, were administered
sequentially in patients with incurable advanced solid tumors
unresponsive to conventional treatment or for which no effective
therapy exists.
Sapacitabine was dosed twice daily for 7 days (Day 1-7) and
seliciclib twice daily for 3 days (Day 8-11). One treatment cycle
is three weeks.
At least 3 patients were enrolled at each escalating dose level.
The first tumor imaging study is conducted after 2 cycles of
treatment and every 3 cycles thereafter. The primary objective of
the study is to determine the MTD and recommended Phase 2 dosing
schedule of the sapacitabine and seliciclib administered
sequentially. The secondary objective was to evaluate the antitumor
activity of sequential treatment and to explore the pharmacodynamic
effect of this treatment in skin and peripheral blood mononuclear
cells.
The abstract can be accessed through the ASCO website, www.asco.org:
"Phase I study of sequential sapacitabine and
seliciclib in patients with advanced solid tumors"
Date/Time: Monday June 4, 2012, 8:00 AM Central
Location: S Hall A2 (Poster Board 14C)
Abstract Number: 3053
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About sapacitabine
Sapacitabine (CYC682), an orally-available nucleoside analogue, is in the SEAMLESS, registration-directed, Phase 3 trial in elderly patients with newly diagnosed acute myeloid leukemia (AML), Phase 2 trials in patients with hematological malignancies, including myelodysplastic syndromes (MDS), cutaneous T-cell lymphoma (CTCL), chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), and non-small cell lung cancer (NSCLC), a Phase 1 trial in combination with seliciclib in patients with advanced solid tumors and an investigator-led, Phase 2/3 study comparing sapacitabine to low dose cytarabine as front-line treatment of elderly patients with AML or high risk MDS unfit for intensive chemotherapy. Sapacitabine acts through a novel DNA single-strand breaking mechanism, leading to production of DNA double strand breaks (DSBs) and/or checkpoint activation. Unrepaired DSBs cause cell death. Repair of sapacitabine-induced DSBs is dependent on the homologous recombination DNA repair (HRR) pathway. Both sapacitabine and CNDAC, its major metabolite, have demonstrated potent anti-tumor activity in preclinical studies.
Over 350 patients have received sapacitabine in Phase 2 studies in AML, MDS, CTCL and NSCLC and over 170 patients in five Phase 1 studies with both hematological malignancies and solid tumors. In June 2009 at the Annual Meeting of the American Society of Hematology (ASH), Cyclacel reported data from a randomized Phase 2, single-agent study of sapacitabine including promising 1-year survival in elderly patients with AML aged 70 years or older. In June 2011 at the Annual Meeting of the American Society of Clinical Oncology (ASCO), Cyclacel reported data from a pilot Phase 1/2 study including promising response rate, low 4-week and 8-week mortality in elderly patients with AML aged 70 years or older receiving sapacitabine alternating with decitabine. The FDA and the European Medicines Agency have designated sapacitabine as an orphan drug for the treatment of both AML and MDS. Sapacitabine is part of Cyclacel's pipeline of small molecule drugs designed to target and stop uncontrolled cell division.
About seliciclib
Seliciclib is an orally-available CDK inhibitor molecule that selectively inhibits multiple enzyme targets, CDK2, CDK7 and CDK9, which are central to the process of cell division and cell cycle control. Seliciclib treatment has been reported to inhibit the two major DNA double-strand break (DSB) repair pathways, homologous recombination DNA repair (HRR) and non-homologous end joining (NHEJ), by reducing expression of components of each pathway (Federico, M., et al, Mol Cancer, 2010, 9, 208). Seliciclib has been evaluated to date in approximately 380 patients and is currently in randomized Phase 2 trials in patients with previously treated lung cancer and nasopharyngeal cancer.
About BRCA Genes and Mutations
Breast cancer susceptibility proteins BRCA1 and BRCA2 are tumor
suppressors that ensure DNA stability and prevent uncontrolled cell
growth in normal cells. BRCA gene mutations are common in breast
and ovarian cancer, but other defects including suppression of
BRCA1/2 expression by promoter hypermethylation can produce HRR
defects in these and other tumors, including NSCLC1 and AML2.
Although BRCA 1/2 mutations are found in approximately 20% of high
grade serous ovarian
cancers,3 around 50% are reported to be HRR-defective due to these
and other modifications of HRR components. 4
Genetic testing for BRCA status is routinely available. BRCA
mutation has been linked to predisposition to breast and ovarian
cancer.
According to the US National Cancer Institute, during her life time
a woman has a 60% chance of developing breast cancer and 15-40%
chance of developing ovarian cancer if she inherits a harmful BRCA
mutation.
These risks are 5 times and over 10 times more likely than for
women without the mutation respectively. Risks are highest with a
family history of multiple cases of breast cancer; cases of both
breast and ovarian cancer; one or more family members with two
primary cancers; Norwegian, Dutch, and Icelandic heritage; or
Ashkenazi (Central and Eastern European) Jewish background. Harmful
BRCA1 mutations may additionally increase a woman's risk of
developing triple-negative breast, cervical, uterine, pancreatic,
and colon cancer. Harmful BRCA2 mutations may increase a woman's
risk of pancreatic, stomach, gallbladder and bile duct cancer, and
melanoma. Men with harmful BRCA1 mutations have an increased risk
of male breast cancer and, possibly, of pancreatic, testicular, and
early-onset prostate cancer. Harmful
BRCA2 mutations may increase a man's risk of developing male
breast, pancreatic and prostate cancer.
About the homologous recombination DNA repair (HRR) pathway
DNA double strand breaks (DSBs) are considered the most lethal
form of DNA damage. The two major DSB repair mechanisms are
homologous recombination DNA repair (HRR) and the intrinsically
error-prone non-homologous end joining (NHEJ). Loss of HRR function
through mutation of HRR pathway components, such as BRCA1 and
BRCA2, are associated with breast, ovarian, prostate and pancreatic
cancers. The incidence of HRR deficiency (HRD or 'BRCAness') in
many tumor types is reported to be significantly greater than that
predicted by BRCA mutations alone. For example, gene mutation or
altered protein levels of many HRR components (including BRCA1 and
BRCA2) can contribute to HRR deficiency in up to 50% of epithelial
ovarian cancers.4 Low protein expression of BRCA1 or BRCA2 was
reported in 57% of NSCLC lung cancer
samples.1 Depletion or inhibition of HRR components (including ATM,
BRCA1, BRCA2, Rad 51 and XRCC3) greatly sensitize tumor cell lines
to sapacitabine-induced cell death, 5 outlining the potential
clinical utility of sapacitabine in patients with HRD tumors.
About Cyclacel Pharmaceuticals, Inc.
Cyclacel is a biopharmaceutical company developing oral
therapies that target the various phases of cell cycle control for
the treatment of cancer and other serious diseases. Sapacitabine
oral capsules is in the SEAMLESS Phase 3 trial being conducted
under an SPA with the FDA as front-line treatment of acute myeloid
leukemia (AML) in the elderly, Phase 2 studies for AML,
myelodysplastic syndromes (MDS), solid tumors including lung
cancer, chronic lymphocytic leukemia and an investigator-led, Phase
2/3 study comparing sapacitabine to low dose cytarabine as
front-line treatment of elderly patients with AML or high risk MDS
unfit for intensive chemotherapy. Cyclacel's pipeline includes
seliciclib oral capsules in Phase 2 studies for the treatment of
lung cancer and nasopharyngeal cancer and in a Phase 1 trial in
combination with sapacitabine. Cyclacel's ALIGN Pharmaceuticals
subsidiary markets directly in the U.S. Xclair(R) Cream for
radiation dermatitis,
Numoisyn(R) Liquid and Numoisyn(R) Lozenges for xerostomia.
Cyclacel's strategy is to build a diversified biopharmaceutical
business focused in hematology and oncology based on a portfolio of
commercial products and a development pipeline of novel drug
candidates. Please visit www.cyclacel.com for additional
information.
1 Lee et al. Clin Cancer Res 2007, 13, 832. Paul et al. J.
Pathol.
2011, 224: 564.
2 Scardocci et al. Brit. J. Cancer 2006, 96: 1108.
3 The Cancer Genome Atlas Research Network. Nature 2011, 474: 609.
4 Mukhopadhyay et al. Clin. Cancer Res. 2010, 16: 2344.
5 Liu, X., et al, Blood, 2010, 116, 1737; Frame, S., et al, Proc. 101st AACR, 2010, Abs. 3502.
Forward-looking Statements
This news release contains certain forward-looking statements
that involve risks and uncertainties that could cause actual
results to be materially different from historical results or from
any future results expressed or implied by such forward-looking
statements. Such forward-looking statements include statements
regarding, among other things, the efficacy, safety and intended
utilization of Cyclacel's product candidates, the conduct and
results of future clinical trials, plans regarding regulatory
filings, future research and clinical trials and plans regarding
partnering activities. Factors that may cause actual results to
differ materially include the risk that product candidates that
appeared promising in early research and clinical trials do not
demonstrate safety and/or efficacy in larger-scale or later
clinical trials, trials may have difficulty enrolling, Cyclacel may
not obtain approval to market its product candidates, the risks
associated with reliance on outside financing to meet capital
requirements, and the risks associated with reliance on
collaborative partners for further clinical trials, development and
commercialization of product candidates. You are urged to consider
statements that include the words "may," "will," "would," "could,"
"should,"
"believes," "estimates," "projects," "potential," "expects,"
"plans,"
"anticipates," "intends," "continues," "forecast," "designed,"
"goal,"
or the negative of those words or other comparable words to be
uncertain and forward-looking. For a further list and description
of the risks and uncertainties the Company faces, please refer to
our most recent Annual Report on Form 10-K and other periodic and
other filings we file with the Securities and Exchange Commission
and are available at www.sec.gov. Such forward-looking statements
are current only as of the date they are made, and we assume no
obligation to update any forward-looking statements, whether as a
result of new information, future events or otherwise.
(C) Copyright 2012 Cyclacel Pharmaceuticals, Inc. All Rights
Reserved.
The Cyclacel logo and Cyclacel(R) are trademarks of Cyclacel
Pharmaceuticals, Inc. Numoisyn(R) and Xclair(R) are trademarks of
Sinclair Pharma plc.
CONTACT: Contact for Cyclacel Pharmaceuticals, Inc.
Investors/Media:
Corey Sohmer, (908) 517-7330, csohmer@cyclacel.com
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Posted: June 2012
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