Abstract OT3-06-02: An initial safety study of gedatolisib plus PTK7-ADC for metastatic triple-negative breast cancer
Authors: Radovich M , Solzak JP , Hancock BA , Storniolo AMV , Schneider BP , Miller KD 
Published: May 2019

Abstract
Background: The PI3K pathway is dysregulated in the majority of triple-negative breast cancer (TNBCs). Contrary to the theory of oncogene addiction, single agent inhibition of the PI3K pathway in TNBC has had only modest activity. Our group has demonstrated preclinically that when PI3K is inhibited, an immediate compensatory up-regulation of the Wnt pathway occurs. The Wnt pathway is known known for its role in cancer metastases and can confer resistance to initial PI3K inhibition. Simultaneous dual targeting of both pathways is highly synergistic against TNBC models in vitro and in vivo.
We have initiated a Phase I clinical trial using Gedatolisib (PI3K/mTOR inhibitor) and PTK7-ADC (Wnt pathway) for patients with metastatic TNBC (NCT03243331). Gedatolisib is a pan-class I isoform PI3K/mTOR inhibitor, and PTK7-ADC is an antibody-drug conjugate against the cell-surface PTK7 protein (Wnt pathway co-receptor) with an Auristatin payload. PTK7 is an attractive second target due to its up-regulation after PI3K inhibition and its known overexpression in TNBC. Further data has shown that the PTK7-payload, Auristatin, is in itself synergistic with Gedatolisib. The combination of using both of these drugs suggests a unique concept of “double synergy”. Where Gedatolisib increases the expression of the target of PTK7-ADC leading to one mechanism of synergy, and the Auristatin payload on PTK7-ADC is synergistic with Gedatolisib providing a second mechanism.
Study Design: This is an open-label, Phase I, dose-escalation study with a 3 + 3 cohort design. The trial will enroll 12-18 patients. 3 cohorts of at least 3 patients will receive Gedatolisib (weekly) & PTK-ADC (q3w) at 110mg+1.4mg/kg, 180mg+1.4mg/kg, and 180mg+2.8mg/kg dose levels.
Eligibility Criteria: This trial enrolls patients with metastatic triple negative (ER-, PgR-, HER2-) or low estrogen expressing (ER and PgR &lt;5%, HER2-) breast cancer. Patients must have received at least one prior chemotherapy for advanced disease and have adequate hematologic, renal, and hepatic function. Patients with previously treated CNS involvement are eligible. Patients with uncontrolled diabetes are excluded, given the potential for hyperglycemia with Gedatolisib. Patients must have disease amenable and consent to biopsy for correlative endpoints.
Objectives: The primary objective is to evaluate the safety of Gedatolisib plus PTK7-ADC. The secondary objective is to evaluate efficacy as determined by objective response rate, clinical benefit at 18 weeks, and progression free survival (PFS). Exploratory objectives will evaluate efficacy in patients with genomic aberrations in the PI3K pathway; and association of tumor DNA, RNA, plasma and circulating tumor cell sequencing with clinical efficacy to identify putative biomarkers.
Correlative Sciences: We are collecting matched pre-/post-treatment tumor biopsies and serial blood samples to determine biomarkers of clinical response to inform subsequent trials. We plan to evaluate: 1) PI3K activity; 2) genomic aberrations in the PI3K pathway; 3) baseline PTK7 expression; 4) PTK7 upregulation after Gedatolisib treatment; and 5) mutations in plasma circulating tumor DNA.
Supported by the BCRF, 100 Voices of Hope, Catherine Peachey Foundation, and Pfizer.
Citation Format: Radovich M, Solzak JP, Hancock BA, Storniolo AMV, Schneider BP, Miller KD. An initial safety study of gedatolisib plus PTK7-ADC for metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT3-06-02.