June 1, 2024
By Catlin Nalley
E7386, a first-in-class anticancer agent, is currently being investigated in combination with lenvatinib in the open-label, global, Phase Ib Study 102 (NCT04008797). During the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, the research team described the ongoing, dose-expansion part of Study 102 in patients with endometrial cancer and hepatocellular carcinoma (Abstract TPS3169).
“The Wnt/β-catenin signaling pathway is involved in the control of gene expression affecting cellular proliferation, differentiation, and polarity,” noted study author Jung-Yun Lee, MD, PhD, in the Department of Obstetrics and Gynecology, Yonsei University College of Medicine, Seoul, South Korea, and colleagues. “E7386 is a first-in-class, orally available modulator of the Wnt/β-catenin signaling pathway.”
Previously, the open-label, Phase I Study 103 explored the tolerability and safety of E7386 in patients with advanced solid tumors and determined that the recommended dose for E7386 monotherapy is 120 mg BID (NCT03833700). The potential of E7386 plus lenvatinib has been demonstrated in several preclinical models.
The dose-escalation portion of the Study 102 trial showed that the combination of E7386 and lenvatinib has a manageable safety profile. The recommended dose for advanced solid tumors was E7386 120 mg BID plus lenvatinib 14 mg (i.e., endometrial cancer) or 20 mg QD.
Study authors reported that the most common treatment emergent adverse events of any grade were nausea, vomiting, hypertension, diarrhea, and proteinuria. The most common TEAEs Grade 3 or higher were proteinuria and gamma-glutamyl transferase level increased. Of the 34 patients who had at least one tumor assessment after receiving the study drug, five achieved a confirmed PR.
The design of the dose-expansion phase of Study 102 for patients with endometrial cancer or hepatocellular carcinoma (HCC) is outlined below.
In the dose-expansion phase of Study 102, researchers will assess the safety, tolerability, and efficacy of E7386 plus lenvatinib among patients with endometrial cancer or HCC.
Patients with HCC (n≈60) will be randomized 2:1 to receive either E7386 plus lenvatinib or lenvatinib monotherapy in 28-day cycles. “E7386 will be administered at 100 mg BID in the combination arm and lenvatinib will be administered QD at 8 mg (if body weight <60 kg) or 12 mg (if body weight ≥60 kg) in both arms,” according to Lee and team. “Patients with HCC will be stratified by geographical region (Western Europe and North America vs. Japan vs. other countries).”>
Endometrial cancer patients (n≈30) will receive only the combination of E7386 120 mg BID plus lenvatinib 14 mg QD.
“Tumors will be assessed by investigator per RECIST v1.1 every 8 weeks from the date of the first dose,” the researchers outlined. “Adverse events will be monitored and recorded for up to 30 days after the last dose or until initiation of a new anticancer therapy, whichever occurs first.”
Eligible patients include adults (≥18 years) with an ECOG performance status of 0-1 and confirmed diagnosis of advanced, unresectable, or recurrent solid tumor. In patients with HCC, other eligibility criteria include the following: a Child-Pugh score of A and a categorization of BCLC Stage B (not amenable to locoregional therapy or refractory to locoregional therapy, and not amenable to a curative treatment) or Stage C.
Additionally, patients with HCC should have also received one prior immuno-oncology (IO)-based regimen and have progressed on/after prior treatment with IO therapy. Patients ineligible for IO therapy should not have underwent prior systemic therapy. Those who received prior lenvatinib are ineligible for inclusion.
“In the endometrial cancer subpart, patients should have disease progression after receiving prior platinum-based chemotherapy and an IO-based therapy for endometrial cancer,” Lee and colleagues stated. “Patients may have received one additional line of platinum-based chemotherapy if given in the neoadjuvant/adjuvant setting, but not exceeding three lines of therapies.
“Patients with endometrial cancer who are ineligible for IO therapy may have received only one prior systemic therapy, including platinum-based chemotherapy,” they continued. “Patients who have received prior lenvatinib therapy will be eligible if they meet protocol-specified criteria.”
This multi-national study is actively recruiting and researchers aim to enroll approximately 90 patients from about 48 investigational sites in the United States, France, Republic of Korea, Japan, and Taiwan. The total study period, according to Lee and colleagues, will be approximately 60 months. As of May 15, 2024, the study authors report that 27 patients with endometrial cancer and 58 patients with HCC have been enrolled.
Catlin Nalley is a contributing writer.