Abstract CT127: Trial in progress: A phase II, open-label, multicenter study of capivasertib, a potent, oral pan-AKT inhibitor in patients with relapsed or refractory B-cell non-hodgkin lymphoma (CAPITAL)
Authors: Wang Michael , Shin Ho-Jin , Herrera Alex F. , Levy Moshe , Kim Wong Seog , Kim Tae Min , Kim Jin Seok , Yoon Dok Hyun , Ribrag Vincent , Canales Miguel , Radford John , El-Sharkawi Dima , Hemmer Brandy , Manwani Richa , Munugalavadla Veerendra , Chen Robert , Mortlock Andrew , Forcina Alessandra , Morschhauser Franck 
Published: June 2022

Background: The PI3K/AKT/mTOR pathway is an established therapeutic target in indolent B-cell non-Hodgkin lymphoma (B-NHL). Several PI3K inhibitors are approved to treat relapsed/refractory (R/R) follicular lymphoma (FL) and, more recently, marginal zone lymphoma (MZL). Nonetheless, potential class-specific and PI3K-isoform-related toxicities may limit their clinical utility. Capivasertib is an oral, potent, selective inhibitor of the 3 AKT isoforms that demonstrated a manageable safety profile (n&gt;1500) and survival benefit in combination with other agents in patients (pts) with solid tumors. Unlike PI3K inhibitors, colitis or pneumonitis have not been a concern with monotherapy. Preclinically, capivasertib was active both in vitro in a large panel of B-NHL cell lines and in vivo in PTEN-null GCB-DLBCL PDX models, where it downregulated the oncogenic factor MYC. In the JVM2 mantle cell lymphoma (MCL) cell line, capivasertib showed superior activity vs PI3Ka/d (AZD8835) and PI3Kb/d (AZD8186) inhibitors. Of note, AKT activation following dysregulation of PTEN has been frequently described in FL (where &gt;85% of tFL or FL/DLBCL exhibited a GCB phenotype). Therefore, capivasertib may represent an effective treatment option for pts with R/R B-NHL.

Trial Design: This modular phase II study will enroll pts in 3 cohorts according to B-NHL type. Core inclusion criteria include: age ≥18 years and ECOG PS ≤2. Module-specific criteria include: cohort 1A: R/R FL after ≥2 prior systemic lines (max 5), including an anti-CD20 monoclonal antibody (mAb) and an alkylating agent; cohort 1B: R/R MZL of splenic, nodal, and extranodal subtypes after ≥2 prior systemic lines (max 5) including ≥1 anti-CD20 mAb; cohort 1C: R/R MCL after ≥2 prior systemic lines (max 4), previously exposed to anti-CD20 mAb and a BTK inhibitor. Pts with FL grade 3B, transformed disease, blastoid or TP53 mutation MCL, active CNS disease, diabetes requiring insulin, or being &lt;3 months post-CD19-directed CAR-T therapy will be excluded.Capivasertib will be administered orally at 480 mg BID with an intermittent schedule (4 days on/3 days off; 28-day cycles) until disease progression or unacceptable toxicity. The primary efficacy endpoint in AACR 2022_Capivasertib TiP Abstracteach cohort is objective response rate based on 2014 Lugano criteria per blinded independent central review. Secondary endpoints include duration of response, progression-free survival, overall survival, patient-reported outcomes, safety, and pharmacokinetics. An interim analysis of safety will occur when approximately 30 pts across all cohorts have been treated for 8 weeks. An interim analysis of efficacy will occur after 28 pts (cohorts 1A+1B) or 24 pts (cohort 1C) have been treated for 4 months. A total of 272 pts are planned across 28 sites in 7 countries globally (US, Europe, and Asia). Recruitment began in October 2021.

Funding: AstraZeneca

Clinical Trial Registration: NCT050080552

Citation Format: Michael Wang, Ho-Jin Shin, Alex F. Herrera, Moshe Levy, Wong Seog Kim, Tae Min Kim, Jin Seok Kim, Dok Hyun Yoon, Vincent Ribrag, Miguel Canales, John Radford, Dima El-Sharkawi, Brandy Hemmer, Richa Manwani, Veerendra Munugalavadla, Robert Chen, Andrew Mortlock, Alessandra Forcina, Franck Morschhauser. Trial in progress: A phase II, open-label, multicenter study of capivasertib, a potent, oral pan-AKT inhibitor in patients with relapsed or refractory B-cell non-hodgkin lymphoma (CAPITAL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT127.