Ramanathan, R. K.

3021 Background: 17DMAG is a water-soluble analog of 17-allylamino-17-demethoxygeldanamycin (17AAG), the first geldanamycin compound to enter clinical trials. 17DMAG causes oncoprotein degradation by binding to heat shock protein 90 (HSP90) & has greater in-vitro activity than 17AAG. In animals treated with 17DMAG, liver toxicity is dose-limiting. The objectives of this first-in-human study are to: establish the dose-limiting toxicity (DLT); recommend a phase 2 dose; & characterize the PK & PD of 17DMAG. Methods: Using a modified accelerated schema, escalating doses of 17DMAG are given IV over 1 h daily x 5 (schedule A) or daily x 3 (schedule B) every 3 weeks. Plasma 17DMAG concentrations during cycle 1 are quantitated by LC/MS. HSP70 & ILK levels in peripheral mononuclear cells are measured by western blot at baseline & 24 h on d 1. Results: 37 pts have been enrolled. On schedule A, dose levels are 1.5, 3, 6, 9, 12 & 16 mg/m2/d (n = 20). On schedule B, the starting dose was 2.5 mg/m2/d. Based on safety information from schedule A, subsequent schedule B dose levels were 14, 19, 25 & 34 mg/m2/d (n = 17). One DLT was noted in schedule A (16 mg/m2) & consisted of reversible liver enzyme elevation. End-of-infusion (EOI) 17DMAG concentrations (33–2074 ng/ml) & AUC0–24 (200–5200 ng/ml x h) increase linearly with dose. Interpatient PK variability was substantial, with CV% of 16–59%. The daily administration schedule precluded precise definition of 17DMAG t1/2 & clearance, but estimates of t1/2 & clearance ranged from 10.8 to 77 h & 19–160 ml/min/m2, respectively. Between 0 & 24 h, 20.5 ± 8.6% (range 4–43.8%) of the administered dose was excreted in urine. HSP70 increased between 0.2 & 3.7 fold above baseline in PBMCs at 24 h at 12, 16, & 25 mg/m2. There is an indication of ILK degradation in 3 of 4 patients evaluated at 25 mg/m2. Conclusions: 17DMAG is well tolerated at current dose levels & maximal tolerated dose has not been reached. 17DMAG plasma PK are linear over the doses delivered to date, & there is evidence of a target effect as manifested by↑HSP70 & ↓ILK. Support: U01CA099168–01, U01CA62502, U01CA69912, R01CA90390 & NIH/NCCR/GCRC grants #5M01 RR 00056 & M01 RR00080 No significant financial relationships to disclose.

4067 Background: N9741 randomized 1691 patients (pts) to seven 5FU, Ox and Iri containing regimens for MCRC. After 20.4 months median follow-up, FOLFOX and IROX improved time to progression (TTP) and overall survival (OS) compared to IFL. Here we update OS and TTP, and report an analysis of factors prognostic of pt outcome. Methods: 5 yr OS and TTP were calculated by Kaplan-Meier per treatment (rx) arm. Pt factors [rx arm, age, gender, prior adjuvant rx, body mass index (BMI), performance status (PS), number of disease sites (#sites), neutrophil count (ANC), hemoglobin, platelets, bilirubin, alkaline phosphatase (ALK), aspartate aminotransferase (AST)] were assessed for univariate association with OS, TTP, response rate (RR), and any grade =3 toxicity. Associated factors were included in multivariate Cox and logistic regression models. Results: After a median follow-up of 4.3 yrs, FOLFOX treated pts were more likely to live 5 yrs, 9.2% versus 5.4% for IROX (p=.016) and 3.8% for IFL (p<.001). Median TTP was also significantly longer in the FOLFOX arm, 9.2 mo vs 6.5 mo for IROX (p=<.001) and 6.0 mo for IFL (p=<.001). The prognostic model found higher PS, ANC and ALK, and more disease sites were prognostic of worse OS (see table ). Age = 70 was associated with poorer survival (HR death 1.33, p=.03), but not TTP, RR, or grade =3 toxicity. FOLFOX rx was the most powerful prognostic factor for TTP and OS. The odds of grade =3 toxicity were significantly higher in FOLFOX treated pts (OR 1.65, p<.001) and lower in men (OR .63, p<.001). No significant interactions between rx arm and pt factors were present, suggesting no factor examined is predictive of rx-specific outcome. Conclusions: 9% 5 yr OS in MCRC pts treated with first-line FOLFOX sets a new benchmark. We confirmed pre-rx PS, WBC, and ALK are prognostic for OS, though FOLFOX rx was the strongest prognostic factor. No factor was associated with differential outcome or toxicity by rx arm, thus these factors cannot be used to guide rx selection. [Table: see text] [Table: see text]

Abstract Background: Nal-IRI (MM-398, nanoliposomal irinotecan) is designed for extended circulation relative to free irinotecan and to exploit leaky tumor vasculature for enhanced drug delivery to tumors. Tumor deposition of nal-IRI and subsequent conversion to SN-38 in both neoplastic cells and tumor associated macrophages (TAM) may positively correlate with response to therapy. In phase I studies of nal-IRI, activity has been shown in metastatic breast cancer (MBC), pancreatic and colorectal cancer. Ferumoxytol (FMX) is an iron-oxide superparamagnetic nanoparticle that has been used off-label for its MRI contrast properties. FMX has long-circulating pharmacokinetics and is taken up by TAMs with similar distribution patterns to nal-IRI in preclinical models. A single site pilot study established the feasibility of performing quantitative FMX MRI. Thirteen patients with advanced cancer (3 with ER/PR+ MBC) were imaged with FMX MRI and treated with nal-IRI. Median tumor lesion FMX uptake in the pilot study was 32.6 and 34.5 μg/mL at 1 h and 24 h, respectively. Lesions with FMX uptake above the median were associated with greater reductions in tumor size following treatment with nal-IRI as determined by CT lesion measurements. The relationship between FMX levels in tumor lesions and nal-IRI activity may serve as a potential biomarker for nal-IRI deposition and response in solid tumors. This study has been expanded to include additional MBC patients to further evaluate the technical feasibility of FMX MRI at multiple study sites, and to evaluate activity of nal-IRI in patients with MBC. Trial Design: Three cohorts of 10 patients with MBC in the following categories will be enrolled: ER and/or PR positive/HER2-negative, triple negative (TNBC) and MBC with brain metastases. An imaging phase will be followed by a treatment phase. The imaging phase consists of a baseline MRI scan, FMX infusion, and follow-up MRI scans at 1-4 and 24 h after infusion. The treatment phase begins 1-6 days after imaging and consists of nal-IRI 80 mg/m2 q2w. A pretreatment biopsy is required for correlative studies. Study Objectives: The primary objective of this multisite expansion is to investigate the feasibility of FMX quantitation in tumor lesions at multiple lesion sites in breast cancer. The secondary objective is to characterize the efficacy of nal-IRI in patients with metastatic breast cancer. Eligibility Criteria: The key inclusion criteria include patients with MBC, ECOG 0 or 1 with adequate bone marrow reserve and no prior topoisomerase 1 inhibitor or anti-VEGF treatment. ER and/or PR positive/HER2-negative and TNBC patients must have had 1-3 prior lines of chemotherapy in the metastatic setting and have at least 2 measurable lesions. Patients with brain metastasis must be neurologically stable and have new or progressive brain metastases after prior radiation therapy with at least one lesion measuring ≥ 1 cm in longest diameter on gadolinium-enhanced MRI. Status: This trial is currently recruiting patients. Citation Format: Sachdev JC, Ramanathan RK, Raghunand N, Anders C, Munster P, Minton S, Northfelt D, Blanchette S, Campbell K, Lee H, Klinz SG, Hendriks BS, Moyo V, Fitzgerald JB, Korn RL. A phase 1 study in patients with metastatic breast cancer to evaluate the feasibility of magnetic resonance imaging with ferrumoxytol as a potential biomarker for response to treatment with nanoliposomal irinotecan (nal-IRI, MM-398). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT3-02-14.