Betty Lawrence

Cortisol production rate. V. Congenital virilizing adrenal hyperplasia

Cortisol secretion rates were estimated by the in vivo isotope dilution technique in 16 patients with congenital virilizing adrenal hyperplasia; the data presented includes those of 2 salt losers previously published. The data were compared with those from age-matched controls. Six patients with the typical pattern of the salt-losing form had low CPRs. A seventh patient, the appearance of whose clinical manifestations was somewhat delayed and who had relatively mild salt loss, had a normal rate. Seven patients with the simple virilizing form had CPRs within the normal range. The eighth and youngest patient, aged 16 days, had a low CPR at a time when moderate transient salt loss was detected. The ninth patient was under ACTH stimulation for one week and had a CPR similar to those of the untreated patients.

Abstract B49: GRN1005 phase I studies: Final results.

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. GRN10059s 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.

Abstract B160: ANG1005: New EPiC compound for the treatment of recurrent malignant glioma

ANG1005 is a new generation taxane created from Angiochem9s Engineered Peptide Compound (EPiC) platform. Studies have shown that ANG1005 gains entry into the brain compartment by targeting the low‐density lipoprotein receptor‐related protein (LRP) which is one of the most highly expressed receptors on the surface of the BBB. Once inside the brain, ANG1005 enters tumor cells using the same receptor‐mediated pathway through LRP, which is upregulated in various cancer cells including malignant glioma cells. Approximately 16,000 new cases of malignant glioma are diagnosed in adults in the United States every year with poor prognosis. A multi‐center, phase I, open‐label, sequential cohort, dose escalation study of ANG1005 in patients with recurrent malignant glioma is ongoing in the US. Study objectives include characterization of safety and tolerability and identification of maximum tolerated dose (MTD). To examine whether or not ANG1005 could be measured in malignant glioma tumors in humans, fresh, excised tumor samples from patients undergoing debulking surgery following administration of one dose of ANG1005 were collected and analyzed. ANG1005 is administered by IV infusion once every 21 days (1 treatment cycle) without premedication. Doses of 30–700 mg/m2 have been evaluated to date; 650 mg/m2 is currently being expanded as MTD. Data including adverse events and hematological parameters indicate that ANG1005 is safe and well tolerated. The most common events occurring at a severity ≥ Grade 2 according to CTCAE, version 3.0 in patients dosed ≥ 300 mg/m2 (n=28) were neutropenia (71% of patients; Grade 4 in 36%), leucopenia (61%; Grade 4 in 11%), infusion reactions (25%; mostly Grade 2 and easily controllable ‐ no cases of Grade 4) and rash (21%; mostly Grade 2 ‐ no cases of Grade 4); these events have been transient and manageable with standard treatments. Neurocognitive data have shown that ANG1005 does not cause cognitive impairment and tests for antibodies demonstrate that ANG1005 does not elicit antibody production even in patients who had reported infusion reactions and/or rashes. Pharmacokinetic data indicate linear ANG1005 bioavailability. Analysis of tumor samples from patients who had received doses of ANG1005 of 200–550 mg/m2 4–6 hours prior to debulking shows a concentration of ANG1005 in tumors relative to plasma of 8 to 379%. Differences between samples are attributed to the different dose levels tested, the range of timing between dosing and tumor extraction and differences in tumor consistencies. Additional analysis revealed that the tumor samples did not grow when cultured in neurospheres. Disease control (≥ stable disease) assessed by MRI was achieved in 60% of patients dosed ≥ 300 mg/m2 including one patient who was progressing on bevacizumab therapy prior to study entry. Tumor stabilization and in some cases significant reduction in tumor size and reversal of neurological deficits were observed in patients with high grade gliomas. Clinical data gathered to date indicate a promising future for the development of ANG1005 for the treatment of patients with malignant glioma. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B160.