Xiaochun Liu

Advanced malignancies treated with a combination of the VEGF inhibitor bevacizumab, anti-EGFR antibody cetuximab, and the mTOR inhibitor temsirolimus

BACKGROUND Bevacizumab and temsirolimus are active agents in advanced solid tumors. Temsirolimus inhibits mTOR in the PI3 kinase/AKT/mTOR pathway as well as CYP2A, which may be a resistance mechanism for cetuximab. In addition, temsirolimus attenuates upregulation of HIF-1α levels, which may be a resistance mechanism for bevacizumab. RESULTS The median age of patients was 60 years (range, 23-80 years). The median number of prior systemic therapies was 3 (range, 1-6). The maximum tolerated dose (MTD) was determined to be bevacizumab 10 mg/kg biweekly, temsirolimus 5 mg weekly and cetuximab 100/75 mg/m2 weekly. Grade 3 or 4 toxicities were seen in 52% of patients with the highest prevalence being hyperglycemia (14%) and hypophosphatemia (14%). Eighteen of the 21 patients were evaluable for response. Three patients were taken off the study before restaging for toxicities. Partial response (PR) was observed in 2/18 patients (11%) and stable disease (SD) lasting ≥ 6 months was observed in 4/18 patients (22%) (total = 6/18 (33%)). In 8 evaluable patients with squamous cell carcinoma of the head and neck (HNSCC) there were partial responses in 2/8 (25%) patients and SD ≥ 6 months in 1/8 (13%) patients (total = 3/8, (38%)). PATIENTS AND METHODS We analyzed safety and responses in 21 patients with advanced solid tumors treated with bevacizumab, cetuximab, and temsirolimus. CONCLUSION The combination of bevacizumab, cetuximab, and temsirolimus showed activity in HNSCC; however, there were numerous toxicities reported, which will require careful management for future clinical development.

Incidence of mucositis in patients treated with temsirolimus-based regimens and correlation to treatment response.

Mucositis may limit the therapeutic window for mammalian target of rapamycin inhibitor-based combination therapy, necessitating treatment interruptions and/or dose reductions. Optimizing treatment or prophylactic interventions for mucositis will enable patients to continue effective treatment while maintaining good quality of life.

Abstract CT046: First-in-human phase 1 study assessing imalumab (BAX69), an anti-oxidized macrophage migration inhibitory factor (oxMIF) antibody in advanced solid tumors

Background: MIF is a pleiotropic cytokine involved in tumor proliferation, invasiveness, angiogenesis, and the proinflammatory microenvironment. oxMIF is the pathogenic form mainly in tumor and its surrounding stroma. Imalumab (BAX69) is a novel recombinant, fully-human, monoclonal antibody that targets oxMIF, inhibiting tumorigenesis. Preclinical data demonstrated that imalumab has antitumor activities and acceptable toxicities. Methods: The primary endpoint of this dose-escalation study (3+3 design) was to assess maximum tolerated dose (MTD). The secondary endpoints were to assess antitumor activity, safety, pharmacokinetics (PK), and pharmacodynamics (PD). Patients (pts) received intravenous (IV) imalumab [28-d cycles; 2 dose schedules (DS)]: biweekly in all solid tumors (DS1); weekly in metastatic colorectal cancer (mCRC), metastatic ovarian cancer (OvCa) and metastatic non-small cell lung cancer (NSCLC) (DS2). Results: As of July 1 2015, 48 pts were treated in this study. DS1 = 19 pts in 6 cohorts (1, 3, 10, 25, 37.5, and 50 mg/kg), and DS2 = 29 pts in 2 cohorts (10 and 25 mg/kg) including expansion (10 mg/kg) into mCRC, OvCa and NSCLC. AUC and Cmax increased with dose. Dose escalation was stopped at 50 mg/kg (DS1) and 25mg/kg (DS2). An MTD was not reached for either DS. One pt reported dose-limiting toxicities: hypersensitivity pneumonitis (DS1; 50 mg/kg). There were no other grade 3 and 4 treatment related adverse events (trAEs). Grade 2 trAEs include: fatigue (n = 2), constipation (n = 1), peripheral edema (n = 1), infusion reaction (n = 1), and urticaria (n = 1). Stable disease (SD) ?4 mo was seen in 7 heavily pre-treated pts, including 1 pt with NSCLC who achieved SD for 13.4 mo. In DS2; Pre- and on-therapy tumor biopsies showed satisfactory tissue penetration of imalumab resulting in target saturation in all biopsy evaluable patients in all 3 tumor types. Biopsies revealed regulation of PI3K-AKT-mTOR downstream signaling, TNF-α signaling, anti-inflammatory cytokines (IL-1 and IL-10), and apoptosis. Based on clinical PK and PD study, 10mg/kg weekly was considered a biologically active dose and sufficient to reach ?95% target binding by the end of first cycle. Conclusions: Imalumab was well tolerated and showed single agent antitumor activity in heavily pretreated pts. An MTD was not reached. Recommended phase II dose (RP2D) is 10 mg/kg IV weekly. NCT01765790 Citation Format: Devalingam Mahalingam, Manish R. Patel, Jasgit C. Sachdev, Lowell L. Hart, Niels Halama, Ramesh K. Ramanathan, John Sarantopoulos, Xiaochun Liu, Salim Yazji, Dirk Jaeger, Deyaa Adib, Randolf Kerschbaumer, Apostolia Maria Tsimberidou. First-in-human phase 1 study assessing imalumab (BAX69), an anti-oxidized macrophage migration inhibitory factor (oxMIF) antibody in advanced solid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT046.

Abstract B191: Target-matched therapies in patients with advanced cervical cancers harboring PIK3CA mutations and/or PTEN loss.

Purpose: To evaluate whether PIK3CA mutations and/or PTEN loss predict better clinical outcomes to phase I trials of PI3K/AKT/mTOR inhibition-based therapies in patients with metastatic, recurrent or refractory cervical cancers. Methods: Outcome analyses were conducted on 36 consecutive patients with advanced cervical cancers who were initially seen in a designated Phase I clinic at MD Anderson Cancer Center from 1/1/2006 to 6/30/2012, and tested for PIK3CA mutations and/or PTEN loss in a CLIA-certified molecular diagnostic laboratory, in accordance with the IRB guidelines. All data were obtained from patients’ electronic medical records. Results: All patients (n=36) had received at least one systemic therapy before the referral. Approximately 50% of tested patients (n=18/36) harbored PIK3CA mutations (n=9/34, 26% including seven E545K, one E542K, and one E545K/D549H in squamous cell carcinoma [7/19, 37%], adenocarcinoma [1/12, 8%] and small cell carcinoma [1/1, 100%]) and/or PTEN loss (n=12, 63%). Six patients were removed from further analyses because they did not enroll to a phase I study (n=2) or had only one negative result while the other test was not done (n=4). At their initial phase I therapy, the patients with PIK3CA mutations and/or PTEN loss (n=18) achieved four PR and seven SD ≥ 6 months (61% CR/PR/SD≥6months) with a median progression-free survival (PFS) of 6.7 months, compared to one CR and one SD ≥ 6 months (17% CR/PR/SD≥6months, p=0.026) with a median PFS of 2.5 months (p=0.001) in patients without PIK3CA mutations and/or PTEN loss (n=12). Analyses in patients receiving mTOR inhibitor-based phase I regimens showed that patients with PIK3CA mutations and/or PTEN loss (n=10) achieved three PR and four SD ≥ 6 months (70% CR/PR/SD≥6months) with a median PFS of 6.6 months, compared to one SD ≥ 6 months (17% CR/PR/SD≥6months, p=0.119) with a median PFS of 3.2 months (p=0.014) in patients without PIK3CA mutations and/or PTEN loss who received mTOR inhibitor-based phase I regimens (n=6); or one PR and three SD ≥ 6 months (50% CR/PR/SD≥6months, p=0.63) with a median PFS of 5.3 months (p=0.86) in patients with PIK3CA mutations and/or PTEN loss who did not receive mTOR inhibitor-based phase I regimens (n=8). Conclusions: The most frequent PIK3CA mutation in patients with advanced cervical cancers was E545K. Matched therapy using mTOR inhibitor-based regimens led to dramatic clinical responses, and a significantly longer PFS in patients with PIK3CA mutations and/or PTEN loss. Thus, targeting aberrant PI3K pathway is warranted for further evaluation in patients with advanced cervical cancers. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B191. Citation Format: Ming-Mo Hou, Xiaochun Liu, Sarina A. Piha-Paul, Filip Janku, Jennifer Wheler, Aung Naing, Diane Bodurka, Kathleen Schmeler, Karen Lu, Ralph Zinner, David Hong, Funda Meric-Bernstam, Razelle Kurzrock, Siqing Fu. Target-matched therapies in patients with advanced cervical cancers harboring PIK3CA mutations and/or PTEN loss. [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 B191.