Abstract OT1-08-04: A first-in-human phase Ia dose escalation study of GDC-0077, a p110a-selective and mutant-degrading PI3K inhibitor, in patients with <i>PIK3CA</i>-mutant solid tumors

Abstract Background: Activating mutations in PIK3CA, encoding the p110α subunit of phosphatidylinositol 3-kinase (PI3K), are highly prevalent in breast cancer and solid tumor malignancies. GDC-0077 is a potent p110α-selective inhibitor with a novel mechanism of action that degrades mutant p110α and anti-tumor activity in PIK3CA-mutant breast cancer xenograft models as a single agent and in combination with anti-estrogens with or without a CDK4/6 inhibitor. An open-label, Phase I dose-escalation study of GDC-0077 monotherapy and GDC-0077 combined with endocrine therapies and palbociclib is underway in patients (pts) with locally advanced or metastatic PIK3CA-mutant solid tumors. Data from the completed single agent dose escalation portion of the trial are presented herein. Methods: This study (NCT03006172) assesses the safety (NCI-CTCAE v4), pharmacokinetics (PK), and preliminary anti-tumor activity (RECIST v1.1) of single agent GDC-0077 administered daily (QD) orally at 6, 9, or 12 mg in 28-day cycles until intolerable toxicity or disease progression. Tumor and ctDNA samples are profiled for relevant signaling and pharmacodynamic (PD) biomarkers. Results: As of the clinical cut-off date of 29 March 2019, 20 pts were enrolled in the single agent arm, all with hormone receptor-positive breast cancer, except for 1 pt with colorectal cancer. Nineteen patients had received ≥ 2 prior lines of therapy for metastatic disease. GDC-0077 MTD was established at 9 mg QD. DLTs occurred in 2 pts at 12 mg (1 Grade 4 hyperglycemia, 1 Grade 3 fatigue). Adverse events (AEs) resulted in dose reduction in 6 pts (30%). The most frequent treatment-related (TR)AEs in ≥ 3 pts (15%) included hyperglycemia (14 pts, 70%), diarrhea (8 pts, 40%), decreased appetite and vomiting (4 pts each, 20%), and alopecia, fatigue, nausea, and weight decreased (3 pts each, 15%). Grade ≥3 TRAEs were hyperglycemia (4 pts, 20%) and lymphopenia, fatigue, nausea, weight loss, and asthenia (1 pt, 5% each). Hyperglycemia was generally manageable with oral anti-hyperglycemic medications. Stomatitis (grouped term) occurred in 4 pts (20%, all Grade 1) and responded to topical corticosteroid treatment. Rash (grouped term) occurred in 3 pts (15%) (1 unrelated Grade 2, otherwise Grade 1). No colitis was reported. Mean half-life (t1/2) of GDC-0077 was 18 hours, with the maximum concentration (Cmax) achieved 2-8 hours after dosing. The preliminary PK profile of GDC-0077 showed low-moderate variability in Cmax and area under the concentration-time curve, and dose proportionality across the tested dose levels. Accumulation with QD dosing regimen was 1.6-2.4 fold. All pts discontinued from treatment due to disease progression (radiographic or clinical). Median GDC-0077 treatment duration was 5.3 months (range 1.1-17.6) and cumulative dose intensity was 97%. Overall, partial response (PR) was observed in 5 pts (25%, range 2-10 lines of prior metastatic therapy), with confirmed PR in 4 pts (20%). The clinical benefit rate was 45% (9 of 20 pts). Decreased PI3K pathway effector expression in paired tumor biopsies and decreased PIK3CA mutant allele frequency were observed over time in the majority of specimens. In addition, 18F-fluorodeoxyglucose-positron emission tomography scans at baseline and after 2 weeks of GDC-0077 showed metabolic responses at all dose levels evaluated. Conclusion: The single agent dose escalation study of the p110α-selective and mutant-degrading inhibitor GDC-0077 demonstrated linear PK, a manageable safety profile, PD modulation of the PI3K pathway, and promising preliminary anti-tumor activity. GDC-0077 at the recommended Phase II dose of 9 mg in combination with endocrine therapies with or without the CDK4/6 inhibitor palbociclib is being investigated in this Phase I study and presented separately. Citation Format: Dejan Juric, Kevin Kalinsky, Mafalda Oliveira, Andres Cervantes, Philippe Bedard, Ian Krop, Erika Hamilton, Peter Schmid, Andrea Varga, Nick Turner, Antoine Italiano, Cristina Saura, Valentina Gambardella, Zachary Veitch, Leslie Dickmann, Naoki Kotani, Jill Fredrickson, Amy Kapp, Katie Hutchinson, Stephanie Royer-Joo, Anjali Vaze, Jennifer Schutzman, Komal Jhaveri. A first-in-human phase Ia dose escalation study of GDC-0077, a p110a-selective and mutant-degrading PI3K inhibitor, in patients with PIK3CA-mutant solid tumors [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT1-08-04.

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