Elsevier

Clinical Colorectal Cancer

Volume 19, Issue 4, December 2020, Pages 311-318.e1
Clinical Colorectal Cancer

Original Study
MOMENTUM: A Phase I Trial Investigating 2 Schedules of Capecitabine With Aflibercept in Patients With Gastrointestinal and Breast Cancer

https://doi.org/10.1016/j.clcc.2020.05.007Get rights and content

Abstract

Background

Although data from preclinical and clinical studies provide a strong rationale for combining capecitabine with anti-angiogenic agents, clinical development of this fluoropyrimidine in combination with aflibercept has lagged behind other treatments. We conducted a nonrandomized, noncomparative, 2-arm, phase I trial to address this unmet need.

Patients and Methods

Patients with chemorefractory gastrointestinal and breast cancer were sequentially recruited into a continuous (Arm A, starting dose 1100 mg/m2/day) or intermittent (Arm B, 2 weeks on/1 week off, starting dose 1700 mg/m2/day) capecitabine dosing arm. Aflibercept was administered at a flat dose of 6 mg/kg every 3 weeks in both arms. A classical 3 + 3, dose-escalation design was used. The primary objective was to establish the maximum tolerated dose, dose-limiting toxicities (DLTs), and recommended dose for phase II trials.

Results

Thirty-eight eligible patients were recruited of whom 33 were assessable for DLTs (15 in arm A and 18 in arm B). Fourteen had colorectal cancer, 8 gastric cancer, and 11 breast cancer. DLTs included grade 2 hand-foot syndrome, grade 2 anorexia considered unacceptable by the patient, and grade 3 hypertension. The recommended dose for phase II trials for capecitabine was established at 1300 mg/m2/day in Arm A and 2500 mg/m2/day in Arm B with treatment-related grade ≥ 3 adverse events occurring in 47% and 50% of patients, respectively. Among 26 assessable patients, the objective response rate was 15.4% in Arm A and 7.7% in Arm B.

Conclusion

Combining capecitabine with aflibercept is feasible and associated with a manageable safety profile and some anti-tumor activity in patients with chemorefractory gastrointestinal and breast cancer.

Introduction

Neo-angiogenesis is a hallmark of cancer, providing the basis for tumor growth, invasion, and metastatic dissemination.1 Over the past 2 decades, a number of agents targeting pro-angiogenic pathways have been developed and ultimately approved for use in many tumor types, either as monotherapy or in combination with other therapies.2 These drugs have generally been shown to be well-tolerated. Although cardiovascular toxicity is potentially concerning, severe or fatal events occur in a minority of patients.3, 4, 5, 6 Furthermore, no significant overlap exists between the toxicity profile of anti-angiogenic and cytotoxic drugs, and the risk of the former enhancing side effects that are primarily caused by the latter is limited overall.

As a result of their unique mechanism of action and manageable safety profile, anti-angiogenics have largely expanded therapeutic options in cancer treatment.2 In many disease settings, including gastrointestinal cancers, adding these drugs to standard chemotherapy has led to better outcomes.7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 Furthermore, these agents have represented ideal companion drugs to test in combination with de-intensified chemotherapy regimens whenever contraindications exist to the use of standard chemotherapy combination treatments. One of the best examples of this was the AVEX trial, which set a new standard of care by randomizing treatment-naive patients with metastatic colorectal cancer aged ≥ 70 years and deemed not suitable for doublet chemotherapy between capecitabine alone or in combination with bevacizumab, an anti-vascular endothelial growth factor (VEGF)-A monoclonal antibody.20 In this study, the addition of bevacizumab to single-agent chemotherapy was associated with outcome results that are comparable overall to historical data of doublet chemotherapy regimens, without substantially increasing toxicity.

Aflibercept is a recombinant fusion protein that exerts anti-angiogenic activity by binding VEGF-A, VEGF-B, and placental growth factor with high affinity.21 In a randomized phase III trial (VELOUR) including patients with metastatic colorectal cancer who had previously been treated with oxaliplatin-based chemotherapy, combining aflibercept with FOLFIRI (folinic acid, 5-fluorouracil, and irinotecan) significantly improved objective response rate (19.8% vs. 11.1%; P = .0001), median progression-free survival (PFS) (6.9 vs. 4.7 months; hazard ratio [HR], 0.76; P < .0001), and median overall survival (OS) (13.5 vs. 12.1 months; HR, 0.82; P = .0032) as compared with FOLFIRI alone.9 As a result, both the European Medicines Agency and the United States Food and Drug Administration approved this agent for use in metastatic colorectal cancer in combination with second-line FOLFIRI chemotherapy. Despite these results and the preclinical evidence suggesting enhancement of the anti-tumor activity of anti-angiogenic drugs by capecitabine,22, 23, 24, 25, 26 data on the combination of this oral fluoropyrimidine with aflibercept are limited.27,28 Furthermore, aflibercept has never been investigated in the clinical setting of breast cancer.

Based on these premises, we conducted MOMENTUM, a phase I clinical trial evaluating the safety and tolerability of 2 schedules of capecitabine in combination with aflibercept in patients with chemorefractory gastrointestinal and breast cancers.

Section snippets

Patient Selection

Eligibility was restricted to patients aged ≥ 18 years with histologically confirmed, unresectable, locally advanced or metastatic gastrointestinal (ie, colorectal, gastric, esophageal, pancreatic, biliary) or breast cancer that were refractory to standard therapy. Patients had to have an Eastern Cooperative Oncology Group performance status of ≤ 1, normal bone marrow and organ function, and a life expectancy of > 12 weeks. The main exclusion criteria included administration of chemotherapy,

Patient Characteristics

Between September 2013 and October 2016, 38 eligible patients were enrolled in the study (17 in arm A and 21 in arm B). Of these, 5 were not evaluable for DLT owing to non–toxicity-related missed doses or early discontinuation of capecitabine (n = 4) and early death (n = 1), which was considered to be secondary to tumor progression. Baseline characteristics of the 33 eligible patients who were assessable for DLTs are reported in Table 1. The median age was 54 years (range, 31-74 years) in arm A

Discussion

In this study, we have shown that combining aflibercept with capecitabine is feasible and associated with a manageable safety profile. By using a 2-arm trial design, we established the RP2Ds for 2 administration schedules of this combination treatment, including a continuous (1350 mg/m2) and a 2-weeks-on/1-week-off (2500 mg/m2) dosing of capecitabine. Encouraging signals of anti-tumor activity and overall efficacy were also observed for both schedules.

Further to the preliminary findings of

Conclusions

Combining aflibercept with the standard intermittent or a metronomic dosing schedule of capecitabine is feasible, associated with a manageable safety profile and no unexpected adverse events. Bearing in mind the small numbers, this combination treatment may have interesting anti-tumor activity.

Disclosure

This study was supported by Sanofi who provided aflibercept and a research grant. A. Deleporte reports travel grants from Amgen and Ipsen. M. Piccart-Gebhart reports board member (scientific board) for Oncolytics; consultant (honoraria) for AstraZeneca, Camel-IDS, Crescendo Biologics, Debiopharm, G1 Therapeutics, Genentech, Huya, Immunomedics, Lilly, Menarini, MSD, Novartis, Odonate, Periphagen, Pfizer, Roche, and Seattle Genetics; research funding from AstraZeneca, Lilly, MSD, Novartis, Pfizer

Acknowledgments

The authors thank all patients who participated in this study and their families.

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    S.C. and A.D. contributed equally to this article as first authors.

    F.S. and A.H. contributed equally to this article as senior authors.

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