|January 26, 2017|
|Verastem Announces Dosing of First Patient in Combination Trial of Defactinib and Avelumab in Patients with Ovarian Cancer|
Phase 1/2 Study Expected to Enroll Approximately 100 Patients at up to 15 sites in the U.S.
The Phase 1/2 multicenter, open-label, dose-escalation and dose expansion study is designed to assess the safety, pharmacokinetics, pharmacodynamics, and initial observations of clinical activity of the avelumab/defactinib combination in patients with recurrent or refractory stage III-IV ovarian cancer. Additional primary objectives of the study include identification of the recommended Phase 2 dose (RP2D), and assessment of the best overall response according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
“Our goal, through this collaboration, is to increase our understanding
of FAK inhibition, and further demonstrate the alliance’s commitment to
exploring a diverse range of novel combinations with avelumab,” said
“Patients with late-stage ovarian cancer are in dire need of effective
new treatments. We are eager to review the results of this important
study as we continue to investigate the potential of avelumab to address
the unmet needs for this hard-to-treat cancer,” said Dr.
FAK is a protein which is often overproduced in tumors, enabling cancer cells to evade attack by the immune system. As reported in Cell, and Nature Medicine, pre-clinical research shows that FAK inhibition can modulate the balance of immune cells in the tumor, increasing the presence of cytotoxic T cells in the tumor and decreasing the presence of immunosuppressive T regulatory cells.1,2
*Avelumab is under clinical investigation and has not been proven to be safe and effective. There is no guarantee any product will be approved in the sought-after indication by any health authority worldwide.
**VS-6063 (defactinib) is under clinical investigation and has not be proven to be safe and effective. There is no guarantee any product will be approved in the sought-after indication by any health authority worldwide.
More About the Phase 1/2 Study
The study is comprised of 2 sequential parts: Part A (Dose Escalation) and Part B (Expansion). In Part A (Dose Escalation), approximately 18 subjects will receive avelumab IV treatment in 28-day cycles (10 mg/kg over approximately 1 hour on Days 1 and 15) and oral defactinib twice-daily (BID) continuously starting on Day 1 of Cycle 1. Subject enrollment will proceed according to a standard 3+3 design. In the absence of dose-limiting toxicity, each subject will receive the study drug regimen for a minimum of 28 days (Cycle 1) and may continue to receive additional cycles of study treatment until disease progression has been documented or unacceptable toxicity or other treatment discontinuation criteria have been met. All subjects in a cohort must have completed at least 1 cycle of dosing before dose escalation involving new subjects entered into the next dose cohort can occur. Based on the safety and PK data obtained in the dose escalation portion of the study, the RP2D of the combination will be determined.
In Part B (Expansion), approximately 80 subjects will be enrolled and will receive avelumab IV treatment in 28-day cycles (10 mg/kg over approximately 1 hour on Days 1 and 15) and oral defactinib at the RP2D dose continuously starting on Day 1 of Cycle 1.
Additional information on the clinical trial can be found at: http://bit.ly/2g6bnXA
About Ovarian Cancer
Globally, ovarian cancer is the seventh most common cancer in women.3 Annually, nearly 239,000 cases are diagnosed worldwide.4 Ovarian cancer may be difficult to diagnose, as symptoms may appear only in the later stages, when the disease has spread beyond the ovaries.4 Outcomes for women with ovarian cancer are generally poor due to most patients presenting with advanced disease.5 The 5-year prevalence of women globally living with ovarian cancer is 22.6 per 100,000.4 Current treatment options for epithelial ovarian cancer may include surgery, radiotherapy, chemotherapy and targeted therapies.6 Women who are unable to undergo treatment with platinum-based chemotherapy, due to resistance or refractory disease, currently have very limited treatment options. Platinum-resistant ovarian cancer is defined as ovarian cancer that recurs within six months of completing primary chemotherapy with a platinum-based medication.7 Platinum-refractory ovarian cancer is defined as ovarian cancer that progresses during treatment with a platinum-based chemotherapy regimen.7 There is still a clear unmet need in ovarian cancer in relation to general disease awareness,4 improving initial investigations in primary and secondary care and novel therapies with demonstrable efficacy.8
Avelumab (also known as MSB0010718C) is an investigational fully human
anti-PD-L1 IgG1 monoclonal antibody. By inhibiting PD-L1 interactions,
avelumab is thought to enable the activation of T-cells and the adaptive
immune system. By retaining a native Fc-region, avelumab is thought to
potentially engage the innate immune system and induce
antibody-dependent cell-mediated cytotoxicity (ADCC). In
Defactinib (VS-6063) is an investigational inhibitor of Focal Adhesion
Kinase (FAK), a non-receptor tyrosine kinase encoded by the PTK-2 gene
that mediates oncogenic signaling in response to cellular adhesion and
growth factors.9 Based on the multi-faceted roles of FAK,
defactinib is used to treat cancer through modulation of the tumor
microenvironment, enhancement of anti-tumor immunity, and reduction of
cancer stem cells.1,2 Defactinib is currently being evaluated
in three separate clinical collaborations in combination with
immunotherapeutic agents for the treatment of several different cancer
types including pancreatic, ovarian, non-small cell lung cancer, and
mesothelioma. These studies are combination clinical trials with
pembrolizumab and avelumab from
Immuno-oncology is a top priority for
This press release includes forward-looking statements about Verastem’s
strategy, future plans and prospects, including statements regarding the
development and activity of VS-6063 (defactinib), Verastem’s FAK and
diagnostics programs generally, the structure of our planned and pending
clinical trials and the timeline for clinical development, our rights to
develop or commercialize our product candidates and our ability to
finance contemplated development activities and fund operations for a
specified period. The words “anticipate,” “appear,” “believe,”
“estimate,” “expect,” “intend,” “may,” “plan,” “predict,” “project,”
“target,” “potential,” “will,” “would,” “could,” “should,” “continue,”
and similar expressions are intended to identify forward-looking
statements, although not all forward-looking statements contain these
identifying words. Each forward-looking statement is subject to risks
and uncertainties that could cause actual results to differ materially
from those expressed or implied in such statement. Applicable risks and
uncertainties include the risks that the preclinical testing of
Verastem’s product candidates and preliminary or interim data from
clinical trials may not be predictive of the results or success of
ongoing or later clinical trials, that data may not be available when we
expect it to be, that enrollment of clinical trials may take longer than
expected, that our product candidates will cause unexpected safety
1. Serrels A et al. FAK Controls Chemokine Transcription, Tregs, and Evasion of Anti-tumor Immunity. Cell 2015; 163 (1): 160–73
2. Jiang H et al. Targeting focal adhesion kinase renders pancreatic
cancers responsive to checkpoint immunotherapy. Nat Med 2016:
3. Ferlay J et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality
Worldwide: IARC CancerBase No. 11 [Internet].
5. NICE. Ovarian Cancer: Recognition and Initial Management. Available
from: https://www.nice.org.uk/guidance/cg122. Accessed
7. Ledermann JA et al. Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013; 24(Suppl 6): vi24–32.
8. Ojalvo LS et al. Emerging immunotherapies in ovarian cancer. Discov Med 2015; 20(109): 97–109.
9. Schaller MD and Parsons JT. Focal adhesion kinase: an integrin-linked protein tyrosine kinase. Trends Cell Biol. 1993 3: 258-62.
10. Sulzmaier FJ et al. FAK in cancer: mechanistic findings and clinical applications. Nature Rev Cancer. 2014 14: 598-610.
11. www.clinicaltrials.gov, NCT02546531
12. www.clinicaltrials.gov, NCT02943317
13. www.clinicaltrials.gov, NCT02758587
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