Abstract B49: GRN1005 phase I studies: Final results.
Authors: Wen Patrick Y. , Drappatz Jan , Brenner Andrew , Mikkelsen Tom , Schiff David , Rosenfeld Steven , Groves Morris , Shen Yijing , Wang Xiaolin , Shing Mona , Lawrence Betty , Castaigne Jean-Paul , Gabrail Nash , Sarantopoulos John , Kurzrock Razelle 
Published: June 2012

Background: Treatment of brain tumors is an unmet medical need due to the inability of most anti-cancer agents to effectively cross the blood brain barrier (BBB). GRN1005 (formerly ANG1005) is a peptide-drug conjugate (PDC) consisting of three molecules of paclitaxel covalently linked to a proprietary 19-amino acid peptide (AngioPep-2) that targets the low-density lipoprotein receptor-related protein 1 (LRP-1), which is expressed on the surface of the BBB and on cells of various tumor types. Studies have shown that GRN1005 is capable of crossing the BBB by receptor-mediated transcytosis via LRP-1. Once in the brain, GRN1005 gains entry into tumor cells by binding to LRP-1 on the tumor cells.

Objectives: GRN1005 is investigated as therapy for patients (pts.) with intra-cranial tumors, including malignant glioma and brain metastases (mets), in 2 phase I studies. The primary objectives of the studies were to determine the maximum tolerated dose (MTD) and to examine the safety and tolerability profile of GRN1005. Secondary objectives included tumor response, pharmacokinetics, and immunogenicity.

Methods: Two phase I, multi-center, sequential cohort, dose escalation studies have been conducted with GRN1005 administered IV at doses from 30 to 700 mg/m2 once every 3 weeks (q3w); 1 cycle is q3w. Study ANG1005-CLN-01 (n = 63) was in pts. with primary brain tumors and Study ANG1005-CLN-02 (n=56) was in pts. with advanced solid tumors (breast, lung, others) in which most had brain mets.

Results: The phase I studies have been completed and GRN1005 at 650 mg/m2 q3w was identified as the MTD in each of the studies.

At MTD, the dose-limiting toxicity (DLT) was neutropenia. The incidence of CTCAE Grade 4 neutropenia was 63% and was of short duration; febrile neutropenia occurred in 3 pts. (8%). Other AEs included peripheral neuropathy (5/38 [13%] Grade 2 and 3/38 [8%] Grade 3) and thrombocytopenia (25/38 [68%] Grades 1–3 and 1/38 [3%] Grade 4). There were 4 cases of Grade 3 infusion reactions at MTD (11%). Across all doses, the overall incidence of infusion reactions of any grade is 13% (15/119). No pre-medication was required with GRN1005 infusion in the phase I studies. Liver toxicity was not observed. There was no evidence of CNS toxicity as measured by neurocognitive testing and neurological examinations; and there was no evidence of anti-drug antibody production. Clinical activity in the phase I studies was observed with GRN1005 therapy in both studies. In Study ANG1005-CLN-01, 1 (6%; n=18) pt. achieved a partial response (PR) at MTD. Additionally, 1 pt. out of 3 in the 700 mg/m2 cohort achieved a complete response and 1 pt. out of 4 in the 420 mg/m2 cohort achieved a PR. In Study ANG1005-CLN-02, 4 of 20 (20%) pts. treated at MTD achieved an overall partial response (PR); some pts. had intra-cranial and extra-cranial lesion responses, despite prior taxane failures. A substudy showed GRN1005 and free paclitaxel concentrations in excised primary brain tumors.

Conclusions: In the GRN1005 phase I studies, single agent clinical activity was observed in pts. with primary brain tumors and in pts. with solid tumor brain metastases, including prior taxane failures; extra-cranial responses were observed along with intra-cranial responses. GRN1005's MTD is 650 mg/m2 q3w, and neutropenia was the DLT. Given the clinical activity and safety/tolerability observed in phase I, GRN1005 as therapy for pts. with intra-cranial tumors is being further investigated in phase 2 studies.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B49.