BACKGROUND:
- Endometrial cancer (EC) is the most common gynecologic cancer in the US and the
incidence peaks around 50-60 years of age. 5-year overall survival in patients with
metastasis is around 20 percent and treatment after the second-line treatment has
not been effective for long-term control.
- Pembrolizumab is approved for microsatellite instability (MSI)-high endometrial
cancer which is rare.
- Pembrolizumab and lenvatinib combination therapy as second-line therapy in patients
with advanced or metastatic EC showed promising antitumor activity. Recently, the
Food and Drug Administration (FDA) approved pembrolizumab and lenvatinib in patients
with advanced endometrial cancer who received prior chemotherapy after decades of
lapse in adding new treatment options with an improved progression free survival
(PFS) 6.6 months (vs 3.8 months in standard care chemotherapy), overall response
rate 30 percent and median duration of response of 9.2 months.
- HER2 is positive in 30 percent of endometrial cancer and anti-HER2 therapy has shown
clinical benefit in metastatic EC. Trastuzumab is used off-label with chemotherapy
and as maintenance.
- An autologous dendritic cell vaccine that is transduced with an adenoviral vector
expressing extracellular domain and transmembrane domain of HER2 (AdHER2DC vaccine)
was well tolerated and showed a preliminary clinical benefit of 33.3 percent among
21 evaluable patients (NCT01730118, total enrolled n=33). No cardiotoxicity was
noted. Immunogenicity analysis in a limited number of patients suggested induction
of both humoral and cellular immune responses.
- The combination of pembrolizumab and lenvatinib in EC showed antitumor activity with
manageable toxicity but still showed the responses in a limited group of patients.
To overcome the resistance to immune checkpoint inhibitors, the combination regimen
to induce the antitumor immune response by the AdHER2 vaccine, control the negative
immune regulators and hostile tumor microenvironment by vascular endothelial growth
factor (VEGF) inhibitor lenvatinib, and an immune stimulatory cytokine IL-15
superagonist N-803 has the potential to make the tumor more responsive to the
immunotherapy creating mutual synergy.
OBJECTIVES:
- Phase I: To estimate recommended Phase II dose (RP2D) of pembrolizumab, lenvatinib,
N-803, and AdHER2DC vaccine in participants with HER2 positive endometrial cancer
- Phase II: To preliminarily assess the efficacy of a combination of pembrolizumab,
lenvatinib, N-803, and AdHER2DC vaccine in participants with HER2 positive
endometrial cancer as determined by the proportion of participants without
progression at 6 months
ELIGIBILITY CRITERIA:
- Age >=18 years.
- Metastatic or locally advanced endometrial cancer with HER2 immunohistochemistry
(IHC) 1+, 2+ or 3+.
- Progressed after at least 1 line of standard of care (SOC) systemic therapy
Participants may have received any number of prior cytotoxic agents.
- ECOG performance status <=2 and adequate organ function.
DESIGN:
- An open-label, two-arm, phase I/II study of pembrolizumab, lenvatinib, N-803, and
AdHER2.
- During Phase I, we will estimate recommended Phase II dose (RP2D) of the lenvatinib
in combination with AdHER2DC vaccine, pembrolizumab, and N-803.
- During Phase II we will continue to evaluate the safety and examine the efficacy of
the study regimen at the RP2D of the lenvatinib in combination with AdHER2 DC
vaccine, pembrolizumab, and N-803.
- Participants will undergo apheresis, and AdHER2DC vaccine will be generated by
transducing the participants monocyte-derived dendritic cells with AdHER2 vector.
- Treatment will be delivered for up to 1 year or until progression or unacceptable
toxicity.
- Up to 27 participants will be treated on this trial.