T-regulatory Cell Depletion with E7777 Combined with Pembrolizumab in Recurrent or Metastatic Solid Tumors

Epithelial ovarian cancer (OC) is the most lethal gynecologic cancer: nearly 22,000 women are diagnosed with OC in the US annually and 63% are expected to die from their disease. The 5-year overall survival rate is unacceptably low at 20-30%, with \> 50% of patients experiencing recurrence of their disease. Recurrent, platinum-resistant OC is characterized by a low response to chemotherapy (\<10-15%) and poor prognosis, with overall survival estimated to be \<12 months. Thus, there is an urgent need to identify novel therapies to improve outcomes for patients with recurrent, platinum resistant OC. The primary focus in this trial is targeting tumor associated immunosuppressive T-regs with E7777 combined with PD-1 inhibitor, pembrolizumab. This trial will enroll patients with solid tumors in the dose escalation portion and specified cohorts in the dose expansion portion. In the Phase I portion, 18-30 patients will be enrolled. In the dose expansion portion, approximately 40 patients (20 in each cohort) will be enrolled. Given the relatively poor prognosis and limited treatment options for these patients, this population is considered appropriate for trials of novel therapeutic candidates.

Immunotherapy with immune checkpoint inhibitors (ICI) has emerged as a promising option in several solid tumors, given its durable response and low toxicities. However, the durable benefit of ICI as monotherapy is limited to certain cancers like melanoma, or cancer with a deficient mismatch repair system. However, in the majority of cancers the response rate is lower. For example, the response rate to anti-programmed cell death protein 1 (PD-1) monotherapy in recurrent platinum-resistant ovarian cancer (PROC) has been underwhelming, with a range of 8-15%. E7777 or denileukin diftitox is a recombinant cytotoxic fusion protein composed of the amino acid sequences for diphtheria toxin fragments A and B (Met1-Thr387)-His and for human interleukin-2 (Ala1-Thr133). Denileukin diftitox has been marketed in the US as ONTAK® (Eisai code name E7272) since 1999 and is indicated for the treatment of patients with persistent or recurrent cutaneous T-cell lymphoma (CTCL) whose malignant cells express the CD25 component of the IL-2 receptor. This open label study will investigate the safety and efficacy of a combined regimen of pembrolizumab with T-regulatory cell depletion and E7777 in patients diagnosed with recurrent or metastatic solid tumors in the second line setting. This study will have 2 stages: dose escalation and dose expansion. In the dose escalation, any solid tumor where pembrolizumab is approved for or felt as an appropriate therapy by treating physician based on prior trials with encouraging activities including (but not limited to): renal cell carcinoma, melanoma, ovarian cancer, MSI-H cancer, endometrial cancer (EC), and non-small cell lung cancer, hepatocellular carcinoma, cervical cancer, urothelial cancer. The expansion cohort will include ovarian cancer and MSI-H cancer cohort. More cohorts can be considered later. The TITE-CRM method of dose assignment will be used, which will improve the quality of the assessment of potential toxicities better than the 3+3 method, and will facilitate the evaluation of efficacy. Participants will be treated until disease progression or unacceptable toxicities and/or dose limiting toxicities. E7777 will be given for 8 cycles and Pembrolizumab will be continued after that.