Kellen L. Meadows

Anti-VEGF Therapies in the Clinic

The development and use of antiangiogenesis agents, particularly those targeting vascular endothelial growth factor (VEGF), has become an integral component of anticancer regimens for many tumor types. This review is intended to highlight some of the most important clinical successes and failures of anti-VEGF therapies, and where possible, to suggest important lessons that have been learned. This review emphasizes data from agents that have been FDA approved and/or have completed phase III studies.

A Phase II Study of Capecitabine, Oxaliplatin, and Bevacizumab in the Treatment of Metastatic Esophagogastric Adenocarcinomas

BACKGROUND Esophageal and gastric cancers often present at an advanced stage. Systemic chemotherapy is the mainstay of treatment, but survival with current regimens remains poor. We evaluated the safety, tolerability, and efficacy of the combination capecitabine, oxaliplatin, and bevacizumab in the treatment of metastatic esophagogastric adenocarcinomas. METHODS Thirty-seven patients with metastatic or unresectable gastric/gastroesophageal junction tumors were enrolled and treated with capecitabine 850 mg/m(2) BID on days 1-14, and oxaliplatin 130 mg/m(2) with bevacizumab 15 mg/kg on day 1 of a 21-day cycle. The primary endpoint was progression-free survival (PFS). Secondary endpoints included response rate (RR) and overall survival (OS). Neuropilin-1 (NRP1) and -2 (NRP2) mRNA expression was evaluated in archived tumor. RESULTS Thirty-five patients were evaluable for efficacy. Median PFS was 7.2 months; median OS was 10.8 months. RR was estimated at 51.4%. The regimen was tolerable with expected drug class-related toxicities. NRP2 mRNA levels significantly correlated with PFS (p = 0.042) and showed a trend toward significance with OS (p = 0.051). Nonsignificant trends for NRP1 were noted for higher expression levels and worse outcome. CONCLUSIONS Bevacizumab can be given safely with chemotherapy in patients with metastatic esophagogastric adenocarcinomas. The combination of capecitabine, oxaliplatin, plus bevacizumab has activity comparable to other bevacizumab-containing regimens in metastatic gastroesophageal cancer.

A phase I study of ABT-510 plus bevacizumab in advanced solid tumors.

Targeting multiple regulators of tumor angiogenesis have the potential to improve treatment efficacy. Bevacizumab is a monoclonal antibody directed against vascular endothelial growth factor and ABT‐510 is a synthetic analog of thrombospondin, an endogenous angiogenesis inhibitor. Dual inhibition may result in additional benefit. We evaluated the safety, tolerability, and efficacy of the combination of bevacizumab plus ABT‐510 in patients with refractory solid tumors. We also explored the effects of these agents on plasma‐based biomarkers and wound angiogenesis. Thirty‐four evaluable subjects were enrolled and received study drug. Therapy was well tolerated; minimal treatment‐related grade 3/4 toxicity was observed. One patient treated at dose level 1 had a partial response and five other patients treated at the recommended phase II dose had prolonged stable disease for more than 1 year. Biomarker evaluation revealed increased levels of D‐dimer, von Willebrand factor, placental growth factor, and stromal‐derived factor 1 in response to treatment with the combination of bevacizumab and ABT‐510. Data suggest that continued evaluation of combination antiangiogenesis therapies may be clinically useful.

A Phase I Multicenter Study of Continuous Oral Administration of Lonafarnib (SCH 66336) and Intravenous Gemcitabine in Patients With Advanced Cancer

We conducted a phase I study to assess safety, pharmacokinetics, pharmacodynamics, and activity of lonafarnib plus gemcitabine. Subjects received oral lonafarnib twice daily and gemcitabine on days 1, 8, and 15 every 28 days; multiple dose levels were explored. Lonafarnib had no apparent effect on gemcitabine PK. Mean lonafarnib half-life ranged from 4 to 7 hr; median Tmax values ranged from 4 to 8 hr. Two patients had partial response; seven patients had stable disease at least 6 months. Oral lonafarnib at 150 mg a.m./100 mg p.m. plus gemcitabine at 1,000 mg/m2 is the maximum tolerated dose with acceptable safety and tolerability.

A Phase I Trial of the IGF‐1R Antibody Ganitumab (AMG 479) in Combination with Everolimus (RAD001) and Panitumumab in Patients with Advanced Cancer

PURPOSE This study evaluated the maximum tolerated dose or recommended phase II dose (RPTD) and safety and tolerability of the ganitumab and everolimus doublet regimen followed by the ganitumab, everolimus, and panitumumab triplet regimen. MATERIALS AND METHODS This was a standard 3 + 3 dose escalation trial. Doublet therapy consisted of ganitumab at 12 mg/kg every 2 weeks; doses of everolimus were adjusted according to dose-limiting toxicities (DLTs). Panitumumab at 4.8 mg/kg every 2 weeks was added to the RPTD of ganitumab and everolimus. DLTs were assessed in cycle 1; toxicity evaluation was closely monitored throughout treatment. Treatment continued until disease progression or undesirable toxicity. Pretreatment and on-treatment skin biopsies were collected to assess insulin-like growth factor 1 receptor and mammalian target of rapamycin (mTOR) target modulation. RESULTS Forty-three subjects were enrolled. In the doublet regimen, two DLTs were observed in cohort 1, no DLTs in cohort -1, and one in cohort -1B. The triplet combination was discontinued because of unacceptable toxicity. Common adverse events were thrombocytopenia/neutropenia, skin rash, mucositis, fatigue, and hyperglycemia. In the doublet regimen, two patients with refractory non-small cell lung cancer (NSCLC) achieved prolonged complete responses ranging from 18 to >60 months; one treatment-naïve patient with chondrosarcoma achieved prolonged stable disease >24 months. In dermal granulation tissue, the insulin-like growth factor receptor and mTOR pathways were potently and specifically inhibited by ganitumab and everolimus, respectively. CONCLUSION The triplet regimen of ganitumab, everolimus, and panitumumab was associated with unacceptable toxicity. However, the doublet of ganitumab at 12 mg/kg every 2 weeks and everolimus five times weekly had an acceptable safety profile and demonstrated notable clinical activity in patients with refractory NSCLC and sarcoma. IMPLICATIONS FOR PRACTICE This trial evaluated the maximum tolerated dose or recommended phase II dose and safety and tolerability of the ganitumab and everolimus doublet regimen followed by the ganitumab, everolimus, and panitumumab triplet regimen. Although the triplet regimen of ganitumab, everolimus, and panitumumab was associated with unacceptable toxicity, the doublet of ganitumab at 12 mg/kg every 2 weeks and everolimus at five times weekly had an acceptable safety profile and demonstrated notable clinical activity in patients with refractory non-small cell lung cancer and sarcoma.

Abstract C61: Phase I Study of pazopanib in combination with the investigational hypoxia-targeted drug TH-302.

Background: Preclinical data demonstrate anti-VEGF agents can induce hypoxia, which may mediate resistance and induce increased tumor invasiveness. TH-302 is an investigational hypoxia-targeted drug; under hypoxic conditions, TH-302 releases the DNA alkylator bromo-isophosphoramide mustard (Br-IPM). In several preclinical models, TH-302 plus an anti-VEGF therapy has greater anti-tumor activity than either treatment alone and this activity was associated with anti-VEGF induced hypoxia. Thus, we evaluated the multi-receptor tyrosine kinase VEGFR inhibitor, pazopanib (Paz) in combination with TH-302 in a phase I dose-escalation study, followed by an expanded cohort to better define the safety, tolerability and preliminary activity of the combination. Methods: Eligible patients (pts) had advanced solid tumors. TH-302 was given intravenously, and Paz was orally administered; cycle length was 28 days. TH-302 was dosed at 340 mg/m 2 in cohort 1 and 480 mg/m 2 in cohort 2 on days 1, 8 and 15; Paz was dosed at the approved dose of 800 mg daily in all cohorts. Dose limiting toxicity (DLT) was assessed in cycle 1. Results: To date, 29 pts have been enrolled; median age 55 years (26-79), median prior treatments =1 (range 0-8). Tumor types include colorectal, ovarian, sarcoma, neuroendocrine, pancreatic, lung, gastric, hurthle cell, and bladder/urothelial cancer. Eleven pts were evaluable for toxicity following dose escalation of TH-302. Initially, 3 pts were enrolled in cohort, one with no DLTs. In cohort 2, two DLTs were observed out of 5 evaluable pts: grade 3 thrombocytopenia and neutropenia lasting over 7 days (n=1) and grade 3 vaginitis (n=1). A total of six evaluable pts were enrolled in cohort 1 with one DLT: grade 2 intolerable esophagitis. Possible grade ≥ 3 treatment-related adverse events (AEs) at any point on study include GI-related toxicities (diarrhea, vomiting), lab abnormalities (hyponatremia, AST elevation), hematologic suppression (anemia, ANC, thrombocytopenia), fatigue, headache, stroke, extremity pain and proctitis. Among 26 treated pts with at least one radiographic restaging, 3 pts experienced a PR: 1 pt each with extraskeletal myxoid chondrosarcoma, ovarian cancer and neuroendocrine cancer; all 3 pts had previously received at least one VEGFR inhibitor. Fifteen additional pts have had stable disease as best response, for a clinical benefit rate (PR +SD) of 69%. Four pts have had sustained disease control ≥6 months. Conclusion: The recommended phase II dose for this combination is the standard dose of Paz at 800 mg daily and TH-302 at 340 mg/m 2 on days 1, 8 and 15 of each cycle. At this dose, Paz in combination with TH-302 has shown promising preliminary activity in several treatment-refractory cancers. If confirmed, these preliminary data support the potential value of co-targeting tumor angiogenesis and tumor hypoxia. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C61. Citation Format: Kellen L. Meadows, Paula H. Lee, Richard F. Riedel, Michael A. Morse, Hope E. Uronis, Gerard C. Blobe, Daniel J. George, Jeffrey Crawford, Herbert I. Hurwitz. Phase I Study of pazopanib in combination with the investigational hypoxia-targeted drug TH-302. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C61.

Abstract B58: Phase I study of the IGF-1R antibody ganitumab (AMG 479) in combination with everolimus in patients with advanced solid tumors.

Background: Preclinical data suggests the combination of IGF-1R inhibitor Ganitumab and mTOR inhibitor everolimus may increase anti-tumor activity compared to each agent alone. Therefore we evaluated the maximum tolerated doses/recommended phase II dose for the doublet combination, Ganitumab (G) plus Everolimus (E) followed by an expanded cohort to better understand the safety and tolerability profile. Methods: For dose escalation, eligible patients had advanced solid tumors with adequate organ function and no increased risk for class-related toxicities. G was given intravenously, and E was orally administered; cycle length was 28 days. G was dosed at 12 mg/kg every 14 days; E was dosed at 5 mg daily in cohort one and 5 mg three times weekly in cohort −1. An intermediate dose of E at 5 mg five times weekly was added to better maximize dose intensity. Dose limiting toxicity (DLT) was assessed in cycle 1. Results: Dose escalation is complete with 17 subjects evaluable for DLT toxicity and 16 evaluable for efficacy. Two out of 5 subjects experienced DLTs in cohort one due to dose holdings related to grade 3 hematologic toxicities: thrombocytopenia and neutropenia plus thrombocytopenia. No DLTs were observed out of 6 subjects in cohort −1; one DLT was observed out of 6 subjects in the intermediate cohort due to dose holding related to grade 2 intolerable skin rash and oral mucositis. Possible grade 3 treatment-related adverse events included neutropenia, thrombocytopenia, elevated AST/ALT, hypertriglyceridemia, vomiting and erythema multiforme minor. There were no grade ≥4 treatment-related toxicities. One non treatment- related death was due to disease progression. Two subjects had clinically significant skin rashes which resulted in protocol discontinuation. Twelve subjects have available efficacy data; 4 subjects have not yet been restaged. Two subjects with refractory NSCLC achieved a complete response. Six additional subjects had stable disease as best response. Conclusion: The recommended phase II dose for this doublet combination is G at 12 mg/kg every two weeks and E at 5 mg five times weekly. At this dose, this novel regimen is well-tolerated with potential activity in NSCLC. Enrollment in the expanded cohort has started. 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 B58.