Yvonne Horneffer

Phase I trial of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), a heat shock protein inhibitor, administered twice weekly in patients with advanced malignancies

PURPOSE Phase I dose-escalation study to determine the toxicity and maximum tolerated dose (MTD) of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), a heat shock protein 90 (Hsp90) inhibitor, administered on a twice weekly schedule in patients with advanced cancer. EXPERIMENTAL DESIGN 17-DMAG was administered as a 1- to 2-h infusion twice weekly in 4-week cycles. An accelerated titration design was followed until toxicity was observed, at which point standard dose-escalation proceeded. MTD was defined as the dose at which no more than one of the six patients experienced a dose-limiting toxicity (DLT). Pharmacokinetics were assessed, and Hsp70 mRNA, whose gene product is a chaperone previously shown to be upregulated following the inhibition of Hsp90, was measured in peripheral blood mononuclear cells (PBMCs). RESULTS A total of 31 patients received 92 courses of treatment. The MTD was 21mg/m(2)/d; 20 patients were enrolled at this dose level. Nine patients had stable disease for a median of 4 (range 2-22) months. Both C(max) and AUC increased proportionally with dose. The most common toxicities were grade 1 or 2 fatigue, anorexia, nausea, blurred vision and musculoskeletal pain. DLTs were peripheral neuropathy and renal dysfunction. Expression of Hsp70 mRNA in PBMCs was highly variable. CONCLUSION Twice-weekly i.v. infusion of 17-DMAG is well tolerated, and combination phase I studies are warranted.

Multihistology, Target-Driven Pilot Trial of Oral Topotecan as an Inhibitor of Hypoxia-Inducible Factor-1α in Advanced Solid Tumors

Purpose: Hypoxia-inducible factor 1 (HIF-1) α is frequently overexpressed in human tumors and is associated with angiogenesis and metastasis. Topotecan, a topoisomerase I inhibitor, has been shown to inhibit HIF-1α expression in preclinical models. We designed a pilot trial to measure HIF-1α inhibition in tumor biopsies from patients with advanced solid tumors overexpressing HIF-1α, after treatment with oral topotecan. Experimental Design: Topotecan was administered orally at 1.6 mg/m2 once daily for 5 days/week for 2 weeks, in 28-day cycles. Objectives were to determine inhibition of expression of HIF-1α and HIF-1 target genes in tumor; to assess tumor blood flow by dynamic contrast–enhanced magnetic resonance imaging (DCE-MRI); and to measure pharmacokinetics. Tumor biopsies were collected at baseline and during the second cycle of treatment. Results: Sixteen patients were enrolled. The dose of topotecan was reduced to 1.2 mg/m2/day due to myelosuppression. Seven patients had paired tumor biopsies. In 4 patients, HIF-1α nuclear staining became undetectable after treatment (7.5%–50% staining at baseline). Decreased levels of VEGF and GLUT-1 mRNA were measured in 4 patients; the changes were concordant with reduction in HIF-1α in 3 patients. Decreased tumor blood flow and permeability were observed by DCE-MRI in 7 of 10 patients after 1 cycle. One patient had a partial response accompanied by inhibition of HIF-1α in tumor and reduction in tumor blood flow on DCE-MRI. Conclusions: This multihistology, target assessment trial of a small molecule inhibitor of HIF-1α showed that topotecan could decrease HIF-1α expression in advanced solid tumors. Clin Cancer Res; 17(15); 5123–31. ©2011 AACR.

Phase I trial of vandetanib and bevacizumab evaluating the VEGF and EGF signal transduction pathways in adults with solid tumours and lymphomas

PURPOSE Inhibition of epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) pathways may result in synergistic antitumour activity. We designed a phase I study to evaluate the combination of vandetanib, an investigational agent with activity against EGF receptor and VEGF receptor 2, and bevacizumab, a monoclonal antibody against VEGF. EXPERIMENTAL DESIGN Patients with advanced solid tumours and lymphomas were enrolled. Objectives were to determine the safety and maximum tolerated dose of the combination, characterise pharmacokinetics, measure angiogenic marker changes in blood, and assess tumour blood flow using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Vandetanib was given orally once daily and bevacizumab intravenously once in every 3 weeks in 21-day cycles utilising a standard dose-escalation design. RESULTS Fifteen patients were enrolled, and a total of 94 cycles of therapy were administered. No protocol-defined dose-limiting toxicities were observed; due to toxicities associated with chronic dosing, hypertension, proteinuria, diarrhoea and anorexia, dose escalation was stopped at the second dose level. We observed one partial response and one minor response; 9 patients experienced stable disease. There were significant changes in plasma VEGF and placental-derived growth factor levels, and decreases in K(trans) and k(ep) were observed by DCE-MRI. CONCLUSION In this trial, we safely combined two targeted agents that cause dual blockade of the VEGF pathway, demonstrated preliminary evidence of clinical activity, and conducted correlative studies demonstrating anti-angiogenic effect. The recommended phase II dose was established as vandetanib 200 mg daily and bevacizumab 7.5 mg/kg every 3 weeks.

Clinical Activity of the γ-Secretase Inhibitor PF-03084014 in Adults With Desmoid Tumors (Aggressive Fibromatosis)

Purpose Desmoid tumors (aggressive fibromatosis) arise from connective tissue cells or fibroblasts. In general, they are slow growing and do not metastasize; however, locally aggressive desmoid tumors can cause severe morbidity and loss of function. Disease recurrence after surgery and/or radiation and diagnosis of multifocal desmoid tumors highlight the need to develop effective systemic treatments for this disease. In this study, we evaluate objective response rate after therapy with the γ-secretase inhibitor PF-03084014 in patients with recurrent, refractory, progressive desmoid tumors. Patients and Methods Seventeen patients with desmoid tumors received PF-03084014 150 mg orally twice a day in 3-week cycles. Response to treatment was evaluated at cycle 1 and every six cycles, that is, 18 weeks, by RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1. Patient-reported outcomes were measured at baseline and at every restaging visit by using the MD Anderson Symptoms Inventory. Archival tumor and blood samples were genotyped for somatic and germline mutations in APC and CTNNB1. Results Of 17 patients accrued to the study, 15 had mutations in APC or CTNNB1 genes. Sixteen patients (94%) were evaluable for response; five (29%) experienced a confirmed partial response and have been on study for more than 2 years. Another five patients with prolonged stable disease as their best response remain on study. Patient-reported outcomes confirmed clinician reporting that the investigational agent was well tolerated and, in subgroup analyses, participants who demonstrated partial response also experienced clinically meaningful and statistically significant improvements in symptom burden. Conclusion PF-03084014 was well tolerated and demonstrated promising clinical benefit in patients with refractory, progressive desmoid tumors who receive long-term treatment.

First-in-Human Phase 0 Trial of Oral 5-Iodo-2-Pyrimidinone-2′-Deoxyribose in Patients with Advanced Malignancies

Purpose: Iododeoxyuridine (IdUrd), a halogenated nucleoside analog, produced clinical responses when administered as a radiosensitizer via continuous intravenous (c.i.v.) infusion over the course of radiotherapy. We conducted a phase 0 trial of 5-iodo-2-pyrimidinone-2′-deoxyribose (IPdR), an oral prodrug of IdUrd, in patients with advanced malignancies to assess whether the oral route was a feasible alternative to c.i.v. infusion before embarking on large-scale clinical trials. Plasma concentrations of IPdR, IdUrd, and other metabolites were measured after a single oral dose of IPdR. Experimental Design: Eligible patients had advanced refractory malignancies. A single oral dose of IPdR was administered per patient and patients were followed for 14 days for safety assessments; dose escalations were planned (150, 300, 600, 1,200, and 2,400 mg) with one patient per dose level and 6 patients at the highest dose level. Blood sampling was conducted over a 24-hour period for pharmacokinetic analysis. Results: There were no drug-related adverse events. Plasma concentrations of IdUrd generally increased as the dose of IPdR escalated from 150 to 2,400 mg. All patients at the 2,400 mg dose achieved peak IdUrd levels of (mean ± SD) 4.0 μmol/L ± 1.02 μmol/L at 1.67 ± 1.21 hours after IPdR administration. Conclusions: Adequate plasma levels of IdUrd were obtained to justify proceeding with a phase I trial of IPdR in combination with radiation. This trial shows the ability of a small, phase 0 study to provide critical information for decision-making regarding future development of a drug. Clin Cancer Res; 19(7); 1852–7. ©2013 AACR.

Abstract CT316: A phase I trial of oral TRC102 (methoxyamine HCl) in combination with temozolomide (TMZ) in patients with relapsed solid tumors

Background: Base excision repair (BER), one of the pathways of DNA damage repair, has been implicated in chemoresistance. TRC102 acts through a novel mechanism to inhibit BER and cause DNA strand breaks, potentiating the antitumor activity of TMZ in preclinical models. We conducted a phase I trial of TRC102 in combination with TMZ to determine the safety, tolerability, and maximum tolerated dose of the combination; to evaluate the pharmacokinetics (PK) of each agent alone and in combination; and to assess DNA damage response (percent nuclear area of γH2AX foci) in circulating tumor cells (CTCs). Methods: Eligible pts were required to have refractory advanced solid tumors that had progressed following standard therapy; ≥ 18 yrs of age; ECOG PS 0-2; and adequate organ function. TRC102 and TMZ were administered orally once daily, D1-5 of q28d cycles; Starting dose level (DL 1) was TRC102 25 mg and TMZ 125mg/m 2 . Accrual to DL6 (TRC102 125 mg; TMZ 150 mg/m 2 ) is ongoing. CTCs were obtained during C1 and on C2D1. Blood samples for PK analysis were obtained during C1. Results: Twenty pts have been enrolled to date; median age 59 yrs (range 45-78 yrs); median # of prior therapies: 3.5 (1-9); Dx: GI (6), HN 2 partial responses by RECIST have been observed to date (≥ 6 cycles; NSCLC and granulosa cell tumor of the ovary). Grade 3/4 toxicities (#pts): neutropenia (2), thrombocytopenia (1), lymphopenia (1), anemia (1), leucopenia (1), hypophosphatemia (1). PK in combination was similar to single agent PK reported for both drugs, with no evidence of a PK interaction. TRC102 levels required for preclinical activity (50ng/mL) were achieved at DL1. T 1/2 of TRC102 was 26 hr. CTC analysis is ongoing. Conclusions: Combination of TRC102 with TMZ is well tolerated and clinical activity was observed with 2 partial responses to date. MTD has not been reached; accrual is ongoing. Paired tumor biopsies to assess for evidence of DNA damage response and apoptosis are planned at the MTD in the expansion phase. Citation Format: Woondong Jeong, Khanh Do, Alice Chen, Jennifer Zlott, Lamin Juwara, Yvonne Horneffer, Robert Kinders, Lihua Wang, Priya Balasubramanian, Larry Anderson, Elad Sharon, Howard Streicher, Richard Piekarz, Barbara Conley, Jerry Collins, James H. Doroshow, Shivaani Kummar. A phase I trial of oral TRC102 (methoxyamine HCl) in combination with temozolomide (TMZ) in patients with relapsed solid tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT316. doi:10.1158/1538-7445.AM2015-CT316

Abstract 3718: A Phase II Study of Sorafenib plus Cetuximab in colorectal cancer (CRC) expressing epidermal growth factor receptor (EGFR) and mutated K-ras

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Background: The presence of K-ras mutation predicts for a lack of response to EGFR-directed therapies in CRC. We hypothesized that a drug capable of inhibiting Raf kinase, which is downstream of Ras, could restore tumor sensitivity to cetuximab. We conducted a Phase II single-arm optimal two-stage design trial of cetuximab, a monoclonal antibody directed against EGFR, in combination with sorafenib, a small molecule inhibitor of VEGFR2 and Raf kinase, in patients with EGFR-positive (+) CRC bearing K-ras mutations. Trial Design: Objectives were to determine clinical benefit rate (CBR) (CR+PR+SD for 4 months) and PFS. Eligible patients were ≥ 18 years old and had histologically documented EGFR+ metastatic CRC bearing K-ras mutations which had recurred or progressed following at least one prior chemotherapy regimen; measurable disease; ECOG PS 0-1; adequate bone marrow, hepatic and renal function. Patients previously treated with an EGFR inhibitor were excluded. Cetuximab was given IV at 400 mg/m2 initially as a loading dose on week 1, followed by 250 mg/m2 weekly, in 28-day cycles. Sorafenib was self-administered orally at 400 mg BID. Radiologic assessment was performed at baseline and every 2 cycles; response was determined based on RECIST criteria. Changes in tumor vascularity were evaluated by dynamic contrast-enhanced MRI (DCE-MRI) at baseline and after 2 cycles. Results: A total of 9 patients received at least 2 cycles of therapy and were evaluable for response. The median age was 51 years (range 21-81 years), and all patients had an ECOG PS of 1 and had received prior FU, oxaliplatin, irinotecan, and bevacizumab. Rash, electrolyte abnormalities, hypertension, and diarrhea were the most common toxicities. Grade 2 and 3 toxicities (number of patients in parentheses) were hypophosphatemia (5), hypokalemia (1), hypomagnesemia (1), acneiform rash (2), hand-foot syndrome (1), diarrhea (3), transaminitis (2), hyperbilirubinemia (1), lymphopenia (6), hypertension (1), anemia (1), and hypoalbuminemia (4). The only grade 4 events were lymphopenia (1) and hypokalemia (1). Although no patients had objective responses, 3 patients had stable disease for 6, 6 and 4 months respectively. DCE-MRI results showed reduction in the parameters of permeability, with decrease in ktrans and kep values. Quantitative biomarker analysis with determination of plasma angiogenic factors is ongoing. Conclusions: Sorafenib in combination with cetuximab is well tolerated in CRC patients and was associated with disease stabilization in 3 of 9 patients with EGFR+ CRC bearing K-ras mutations. Sorafenib plus cetuximab may have a role in the treatment of patients with CRC bearing Kras mutations. We have met the response goals for the first stage of the trial, and accrual continues for the second stage. Funded by NCI Contract No. HHSN261200800001E. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3718.