Mark Jeffery

Randomized, Controlled Trial of Irinotecan Plus Infusional, Bolus, or Oral Fluoropyrimidines in First-Line Treatment of Metastatic Colorectal Cancer: Results From the BICC-C Study

PURPOSE This phase III study compared the safety and efficacy of the following three different irinotecan-containing regimens in the first-line treatment of metastatic colorectal cancer: irinotecan plus infusional fluorouracil (FU)/leucovorin (LV) (FOLFIRI), irinotecan plus bolus FU/LV (mIFL), and irinotecan plus oral capecitabine (CapeIRI). PATIENTS AND METHODS A total of 430 previously untreated metastatic colorectal cancer patients were randomly assigned to receive FOLFIRI (n = 144), mIFL (n = 141), or CapeIRI (n = 145). Patients were concurrently randomly assigned to a double-blind treatment with celecoxib or placebo. After a protocol amendment, an additional 117 patients were randomly assigned to either FOLFIRI plus bevacizumab (FOLFIRI+Bev; n = 57) or mILF plus bevacizumab (mIFL+Bev; n = 60), whereas the CapeIRI arm was discontinued. The primary study end point was progression-free survival (PFS), with secondary end points of overall survival (OS), response rate, and toxicity. RESULTS Median PFS was 7.6 months for FOLFIRI, 5.9 months for mIFL (P = .004 for the comparison with FOLFIRI), and 5.8 months for CapeIRI (P = .015). Median OS was 23.1 months for FOLFIRI, 17.6 months for mIFL (P = .09), and 18.9 months for CapeIRI (P = .27). CapeIRI was associated with higher rates of severe vomiting, diarrhea, and dehydration. After the amendment to add bevacizumab, the median survival time has not yet been reached for FOLFIRI+Bev and was 19.2 months for mIFL+Bev (P = .007). FOLFIRI+Bev was associated with a higher rate of > or = grade 3 hypertension than mIFL+Bev. CONCLUSION FOLFIRI and FOLFIRI+Bev offered superior activity to their comparators and were comparably safe. An infusional schedule of FU should be the preferred irinotecan-based regimen in first-line metastatic colorectal cancer.

5,6-Dimethylxanthenone-4-Acetic Acid in the Treatment of Refractory Tumors: a Phase I Safety Study of a Vascular Disrupting Agent

This phase I safety study aimed to identify the optimal dose of the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) for combination studies. Using a crossover design, 15 patients with refractory tumors were allocated randomly to receive six sequential doses of DMXAA (300, 600, 1,200, 1,800, 2,400, and 3,000 mg m−2), each given once-weekly as a 20-minute i.v. infusion. The drug was generally well tolerated. Transient, moderate increases in the heart rate–corrected cardiac QT interval occurred at the two highest doses. DMXAA produced transient dose-dependent increases in blood pressure. Transient, dose-related visual disturbances occurred at the two highest doses. No significant changes in Ktrans and kep were observed but Ve, a secondary dynamic contrast–enhanced magnetic resonance imaging variable, increased significantly after giving DMXAA. At 1,200 mg m−2, the Cmax and the area under the concentration-time curve over 24 hours for total and free DMXAA plasma concentrations were 315 ± 25.8 μg/mL, 29 ± 6.4 μg/mL·d, 8.0 ± 1.77 μg/mL, and 0.43 ± 0.07 μg/mL·d, respectively. Plasma levels of the vascular damage biomarker 5-hydroxyindoleacetic acid increased in the 4 hours after treatment in a dose-dependent fashion up to 1,200 mg m−2, with a plateau thereafter. Doses in the range of 1,200 mg m−2 have been selected for further studies (phase II combination studies with taxanes and platins are under way) because this dose produced no significant effect on heart rate–corrected cardiac QT interval, produced near maximum levels of 5-hydroxyindoleacetic acid, achieved DMXAA plasma concentrations within the preclinical therapeutic range, and was well tolerated.

Comorbidity, age and overall survival in cetuximab-treated patients with advanced colorectal cancer (ACRC)—results from NCIC CTG CO.17: a phase III trial of cetuximab versus best supportive care

BACKGROUND the interplay between comorbidity, age and performance status (PS) as predictors of outcome in advanced colorectal cancer (ACRC) is poorly understood. We examined these factors as predictors of treatment toxicity and outcome in cetuximab-treated patients with ACRC. PATIENTS AND METHODS comorbidity was independently evaluated using the Charlson Comorbidity Index (CCI), a validated measure of comorbidity based on the presence of medical conditions weighted according to their effect on mortality. CCI score was correlated with clinical and outcome data. RESULTS five hundred and seventy-two patients were included; 41% were ≥ 65 years and 25% had comorbidities at randomization. In multivariate analysis (MVA) of all covariates, only older age was associated with greater comorbidity (P = 0.008). Overall survival (OS) was significantly better for patients with greater comorbidity in univariate analysis (P = 0.047). Conversely, better PS was associated with better OS in MVA (hazard ratio 1.92 for PS = 2 versus PS = 0, P < 0.0001). Age was not associated with OS (P = 0.13). Elderly patients had significantly less grade ≥ 3 vomiting (P = 0.034) but more dyspnea (P = 0.005). Patients with greater comorbidity had significantly less grade ≥ 3 vomiting (P =  0.002) but more non-neutropenic fever (P = 0.005). CONCLUSION better PS was associated with improved OS. For patients with good PS, restricting cetuximab use in the setting of significant comorbidity does not appear justified.

Quality of life in patients with K-RAS wild-type colorectal cancer: the CO.20 phase 3 randomized trial.

The CO.20 trial randomized patients with K‐RAS wild‐type, chemotherapy‐refractory, metastatic colorectal cancer to receive cetuximab (CET) plus brivanib alaninate (BRIV) or CET plus placebo (CET/placebo).

Transient Retinal Effects of 5,6-Dimethylxanthenone-4-acetic Acid (DMXAA, ASA404), an Antitumor Vascular-Disrupting Agent in Phase I Clinical Trials

PURPOSE 5,6-Dimethylxanthenone-4-acetic acid (DMXAA), an anticancer vascular-disrupting agent, has induced transient visual symptoms in some patients. Exploratory investigations were undertaken to characterize the visual disturbances in two consecutive phase I trials. METHODS Assessments were made in 21 patients before and immediately after a 20-minute IV infusion of DMXAA, including visual acuity, funduscopy, color discrimination, pattern electroretinography (PERG), pattern visual-evoked potentials (VEP), and full-field electroretinography (ERG). Evaluation of late effects was undertaken subsequently in 12 patients before and after 6 weeks of IV DMXAA at one dose per week. RESULTS Frequency and intensity of transient visual disturbance increased with DMXAA dose, occurring in two thirds of patients at 3000 mg x m(-2). Symptoms included blurring, flickering, fragmentation, alteration of colors, and contrast and mild photosensitivity, starting during the infusion and resolving completely, usually within 60 minutes. Visual acuity was unchanged but color discrimination was perturbed. Dose-dependent increases in PERG P50 implicit time by up to 23 ms returned toward baseline values within 90 minutes. Prominent transient changes on ERG included prolonged scotopic rod and 30-Hz flicker implicit times and reduced 30-Hz flicker amplitude. In the second trial, no clinically significant sustained effects were detected, although an increase in bright flash a-wave implicit time (P = 0.022) was seen on whole-group analysis. In vitro studies showed nonspecific phosphodiesterase inhibition by DMXAA. CONCLUSIONS DMXAA induced acute, transient disturbance of retinal activity consistent with phosphodiesterase inhibition. No clinically significant cumulative effects were noted and most effects occurred at doses higher than those used in ongoing clinical trials (ClinicalTrials.gov numbers, NCT00856336, NCT00863733, and NCT00003697).

Abstract CT110: Randomized phase II study of duligotuzumab + FOLFIRI versus cetuximab + FOLFIRI in 2nd-line patients with KRAS wild-type (wt) metastatic colorectal cancer (mCRC)

Background: Duligotuzumab (MEHD, MEHD7945A) is a novel dual-action humanized IgG1 antibody that blocks EGFR and HER3 binding, inhibiting all major ligand-dependent HER complex signaling. MEHD is active in multiple tumor models, including models resistant to anti-EGFR or anti-HER3. Emerging data in CRC suggest a role for HER3 in de novo and acquired resistance to anti-EGFR therapy. Methods: This open-label, randomized Phase II study enrolled patients (pts) with KRAS exon 2 wt mCRC who progressed on/after oxaliplatin-containing chemotherapy. Pts received a combination of MEHD (1100 mg IV, q2w) or cetuximab (400 mg/m2 load, 250 mg/m2 IV, q1w) + FOLFIRI (q2w) until progression or intolerable toxicity. Endpoints included progression-free survival (PFS), and objective response rate (ORR), overall survival (OS), and adverse events (AEs). Tumor samples were mandatory and underwent biomarker analysis for ERBB3, NRG1 and EGFR ligand expression by qRT-PCR, and ERBB3 by IHC. The primary efficacy analysis was conducted in patients with RAS wt tumors (no mutations detected in KRAS or NRAS exons 2, 3; exon 4 mutations pending). Results: Of 134 randomized patients, 98 were RAS ex2/3 wt (53 MEHD); median age 63 years, ECOG 0-1. As of 21Aug14, 11 pts remain active. Efficacy results (Table) show no benefit of MEHD + FOLFIRI; ORR was lower in the MEDH arm. No relationship was seen between PFS or ORR and mRNA expression for ERBB3 or NRG1, or ERB3 expression by IHC. There were fewer rash events of any grade in the MEHD arm (79% and 93%) but more diarrhea (89% and 66%). Incidence of Grade ≥ 3 AEs was similar between arms (87% and 89%); however, the frequency of SAEs was higher in the MEHD arm (55% and 48%). Cumulative dose intensity and duration of treatment with FOLFIRI were lower in the MEHD arm. Conclusions: MEHD + FOLFIRI did not improve outcomes of pts with RAS ex2/3 wt mCRC compared to cetuximab + FOLFIRI. Updated efficacy, safety and biomarker data will be presented. Citation Format: Andrew G. Hill, Michael Findlay, Matthew Burge, Christopher Jackson, Pilar Garcia Alfonso, Leslie Samuel, Vinod Ganju, Meinolf Karthaus, Alessio Amatu, Mark Jeffery, Maria DiBartolomeo, John Bridgewater, Andrew Coveler, Manuel Hidalgo, Amy V. Kapp, Roxana Sufan, Bruce McCall, Elicia Penuel, Andrea Pirzkall, Josep Tabernero. Randomized phase II study of duligotuzumab + FOLFIRI versus cetuximab + FOLFIRI in 2nd-line patients with KRAS wild-type (wt) metastatic colorectal cancer (mCRC). [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 CT110. doi:10.1158/1538-7445.AM2015-CT110

Phase II Study of the Dual EGFR/HER3 Inhibitor Duligotuzumab (MEHD7945A) versus Cetuximab in Combination with FOLFIRI in Second-Line RAS Wild-Type Metastatic Colorectal Cancer

Purpose: Duligotuzumab is a dual-action antibody directed against EGFR and HER3. Experimental Design: Metastatic colorectal cancer (mCRC) patients with KRAS ex2 wild-type received duligotuzumab or cetuximab and FOLFIRI until progression or intolerable toxicity. Mandatory tumor samples underwent mutation and biomarker analysis. Efficacy analysis was conducted in patients with RAS exon 2/3 wild-type tumors. Results: Of 134 randomly assigned patients, 98 had RAS ex2/3 wild-type. Duligotuzumab provided no progression-free survival (PFS) or overall survival (OS) benefit compared with cetuximab, although there was a trend for a lower objective response rate (ORR) in the duligotuzumab arm. No relationship was seen between PFS or ORR and ERBB3, NRG1, or AREG expression. There were fewer skin rash events for duligotuzumab but more diarrhea. Although the incidence of grade ≥3 AEs was similar, the frequency of serious AEs was higher for duligotuzumab. Conclusions: Duligotuzumab plus FOLFIRI did not appear to improve the outcomes in patients with RAS exon 2/3 wild-type mCRC compared with cetuximab + FOLFIRI. Clin Cancer Res; 24(10); 2276–84. ©2018 AACR.

Abstract B78: A Phase Ib study of demcizumab (DEM, anti-DLL4) with gemcitabine (GEM) in patients with first line locally advanced or metastatic pancreatic cancer.

Background: Delta-like ligand 4 (DLL4) is a ligand that activates the Notch pathway which is important for cancer stem cell (CSC) survival. DEM is a humanized IgG2 anti-DLL4 antibody that has been shown to inhibit tumor growth and decrease CSC frequency in minimally passaged human xenograft models. In addition, inhibition of DLL4 has also been shown in preclinical studies to cause dysfunctional sprouting of new vessels resulting in an antiangiogenic effect. DEM also showed synergistic activity when combined with GEM in human pancreatic tumor-derived xenograft models. Material and Methods: Patients with first line stage III or IV pancreatic cancer received DEM (2.5 every 2 or 4 wks or 5 mg/kg every 4 wks) and GEM 1000 mg/m2 7 of the 1st 8 wks and then 3 of every 4 wks until disease progression. The primary objective was to determine the maximum tolerated dose of DEM. Other objectives included: safety, efficacy, immunogenicity, pharmacokinetic, and biomarkers of Notch signaling and CSCs. Results: Twenty four patients were enrolled; 8 pts received 2.5 mg/kg every 2 wks, 8 received 2.5 mg/kg every 4 wks and 8 received 5 mg/kg every 4 wks of DEM. The median age was 65.5 yrs. Three (12.5%) and 21 (87.5%) patients had stage III and IV disease, respectively. Seven, 16 and 1 patients were ECOG performance status 0, 1, and 2, respectively. Related adverse events (all grades) in ≥10% of patients included: fatigue (29%), hypertension (29%), vomiting (29%), nausea (25%), thrombocytopenia (21%), decreased appetite (21%), increased B-type natriuretic peptide (BNP) (13%), anemia (13%), peripheral edema (13%), pulmonary hypertension (13%), dizziness (13%) and rash (13%). The hypertension was successfully managed with oral anti-hypertensives. Increased BNP values appear to be an early indicator of the cardiac effects of DEM and mildly elevated values are being used to initiate cardioprotective therapy with an ACE inhibitor or carvedilol. One patient who received 5 mg/kg developed reversible pulmonary hypertension and heart failure on study day 143. As a result, the duration of DEM will be limited to 70 days in subsequent cohorts and paclitaxel protein-bound particles will also be added to the regimen. Four of 16 (25%) evaluable patients had a RECIST partial response and 7 had stable disease. The median progression free survival for the 5 mg/kg cohort was 5.9 months. The pharmacokinetic and immunogenicity samples are being analyzed and these data will be presented. Conclusion: DEM plus GEM was generally well tolerated with fatigue, hypertension and vomiting being the most common drug related adverse events. The duration of demcizumab therapy is being limited to 70 days in subsequent cohorts due to cardiopulmonary toxicity which was observed following more prolonged administration. Encouraging early clinical activity has been observed. Subsequent cohorts will include paclitaxel protein-bound particles. Enrollment is ongoing and updated results will be presented. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B78. Citation Format: Antonio Cubillo, Michael Jameson, Enrique Grande, Francis Parnis, Peter Grimison, Prasad Cooray, Mark Jeffery, Robert Stagg, Jakob Dupont, Niall Tebbutt. A Phase Ib study of demcizumab (DEM, anti-DLL4) with gemcitabine (GEM) in patients with first line locally advanced or metastatic pancreatic cancer. [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 B78.