The Efficacy of T-regulatory Cell Depletion with E7777 Combined with Immune Checkpoint Inhibitor, Pembrolizumab, in Recurrent or Metastatic Solid Tumors: Phase I/II Study
Alexander B Olawaiye, MD
Summary
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.
Description
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 rec…
Eligibility
- Age range
- 18+ years
- Sex
- Female
- Healthy volunteers
- No
Inclusion Criteria: * Ability to comply with the study protocol, in the investigator's judgment * Histologically or cytologically confirmed solid tumors (cutaneous melanoma, non-small cell lung cancer, renal cell carcinoma, endometrial cancer, ovarian cancer, MSI-H solid tumors (deficient mismatch repair system or other solid tumors) that have progressed on or refractory to standard of care therapies for their disease * Phase I dose escalation phase * Advanced metastatic or recurrent solid tumors (where pembrolizumab is approved and/or have shown efficacy) that have progressed on or refrac…
Interventions
- DrugPembrolizumab
Pembrolizumab is a humanized monoclonal immunoglobulin (Ig) G4 antibody that inhibits lymphocytes PD-1 receptors, blocking the ligands that would deactivate it and prevent an immune response, allowing the immune system to target and destroy cancer cells.
- DrugE7777
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), 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.
Location
- UPMC Hillman Cancer CenterPittsburgh, Pennsylvania