Abstract OT3-05-01: Adaptive Multi-Drug Treatment of Evolving Cancers (AMTEC): A Phase II, Open-Label, Study of Olaparib in Combination with either Durvalumab, Selumetinib or Capivasertib, or Ceralasertib Monotherapy in Patients with Metastatic TNBC
Authors: Hobbs Evthokia , Mills Gordon , Lim Jeong , Klinger Marlana , Siex Kiara , Huszti Sidney , Yang Annie , Galipeau Danielle , Zheng Christina , Murray Lauren , Goodford Becky , Marter-Sanders Nicholas , Olson Anastasiya , Stommel Jayne , Johnson Brett , Keck Jamie , Kong Ben , Solanki Allison , Goodyear Shaun , Corless Christopher , Gray Joe , Zahi Mitri 
Published: March 2023

BACKGROUND PARP inhibitors (PARPi) afford a rational therapeutic strategy in metastatic TNBC (mTNBC) due to the high incidence of dysregulated DNA damage repair mechanisms and high-level genomic instability that resemble tumors originating in germline BRCA-mutated carriers. However, PARPi monotherapy has limited efficacy in BRCA wild-type mTNBC; in BRCA mutant disease following initial response, compensatory mechanisms inevitably restore replication fork protection. AMTEC leverages pre- and on-therapy biopsies from a 4-week PARPi monotherapy run-in period for personalized biomarker-driven patient selection to interdict adaptive resistance to the PARPi. Data from our pilot study (NCT03544125) and from Arm 1 of AMTEC (olaparib + durvalumab) identified PI3K-AKT, RAS-MEK, and ATR/CHK1/WEE1 as targetable pathways contributing to PARPi adaptive resistance in individual participants. Clinically validated assays (DNA, RNA, and protein) enable the identification of cellular mechanisms of PARPi sensitivity and resistance in individual patients and further reveal combined drug treatments that could prevent emergence of PARPi resistance. METHODS AMTEC is a non-comparative, multi-arm, open-label, phase II study to assess the efficacy of combining olaparib (ola) with durvalumab (dur), or MEKi, selumetinib (sel), or AKTi, capivasertib (cap), or monotherapy with ATRi, ceralasertib, (cer mono) in mTNBC patients. Participants with biopsy proven mTNBC (ER&lt; 10%, PR&lt; 10%, and HER-2 non-amplified), AR&lt; 80% are eligible. - Participants undergo a pre-treatment biopsy, then start a 28-day induction with ola (300 mg PO BID, D1-28). On C1D14, patients undergo a repeat, on-treatment biopsy. Clinically validated assays (DNA, RNA, protein) from both biopsies inform patient assignment to a specific ola combination arm starting on C2D1: - Arm 1 tumor immune activated: ola + dur (1500 mg IV Q4W) - Arm 2 RAS-MEK-ERK pathway activation: ola + sel (BSA-based BID D1-28) - Arm 3 PI3K-AKT pathway activation: ola + cap (400 mg PO BID, 4 days on/3 days off) - Arm 4: If not eligible for Arms 1-3 (per biomarker selection criteria): Cer mono (240 mg PO BID D1-14) Endpoints: The primary endpoint is objective response rate (ORR per RECIST 1.1). Secondary endpoints include safety and toxicity, clinical benefit rate, duration of response, and survival. Statistical Methods: - Arm 1 will enroll 28 patients to detect an ORR difference of 20% (H0: π = 0.15 and Ha: π =0.35). Arm 1 will continue on to stage 2 if ORR ≥3 of the first 15 patients. The null hypothesis for Arm 1 is rejected if ≥ 7/28 patient achieve a response. - Arms 2, 3, and 4, will each enroll 22 patients to detect an ORR difference of 25% (H0: π = 0.15 and Ha: π =0.40). Arms 2, 3, and 4 will each continue on to stage 2 if ORR ≥2 of first 11 patients in each arm, respectively. The null hypothesis for Arm 2, 3, and 4 is rejected if ≥ 7/22 patients achieve a response in each arm, respectively. For arms 2 and 3, if there are ≥5/11 responses, the trial will open a biomarker negative expansion cohort for each arm (N = 19 patients/arm). ENROLLMENT The study was activated on 1/7/2019. Arm 1 met pre-specified interim analysis criteria in 12/2020, and accrual to stage 2 began in 1/2021. Arms 2, 3, and 4 start enrolling in Q4 of 2022. Up to 132 patients will be enrolled. Clinical trial information: NCT03801369 Contact information: For more information or to refer a patient, email hobbev@ohsu.edu

Citation Format: Evthokia Hobbs, Gordon Mills, Jeong Lim, Marlana Klinger, Kiara Siex, Sidney Huszti, Annie Yang, Danielle Galipeau, Christina Zheng, Lauren Murray, Becky Goodford, Nicholas Marter-Sanders, Anastasiya Olson, Jayne Stommel, Brett Johnson, Jamie Keck, Ben Kong, Allison Solanki, Shaun Goodyear, Christopher Corless, Joe Gray, Mitri Zahi. Adaptive Multi-Drug Treatment of Evolving Cancers (AMTEC): A Phase II, Open-Label, Study of Olaparib in Combination with either Durvalumab, Selumetinib or Capivasertib, or Ceralasertib Monotherapy in Patients with Metastatic TNBC [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-05-01.