Efficacy and Safety of Ferric Carboxymaltose Injection in Reducing Anemia in Patients Receiving Chemotherapy for Non-Myeloid Malignancies: A Phase 3, Placebo-Controlled Study (IRON CLAD)
Authors: Gilreath Jeffrey A. , Makharadze Tamta , Boccia Ralph V. , Krupa Anna , Henry David H. 
Published: November 2019

Background: In patients with chemotherapy-induced anemia (CIA), erythropoiesis stimulating agents (ESAs) are effective but are associated with potentially serious side effects, such as venous thromboembolism (VTE). The addition of iron to ESA therapy improves hematologic response, reduces risk of red cell transfusion, and is well tolerated (Mhaskar 2016). This raises the question as to whether intravenous (IV) iron alone accomplishes the same goals in patients with cancer (PwC). Several observational studies evaluating IV iron monotherapy in PwC receiving chemotherapy have demonstrated increases in hemoglobin (Hb) concentrations and/or reductions in transfusion rates, (Dangsuwan 2010, Kim 2007, Hedenus 2014) suggesting that IV iron monotherapy is a feasible treatment option for patients with CIA. However, prospective, randomized, placebo-controlled trial data evaluating the effect of IV iron in PwC and CIA has yet to be produced.
This is the first randomized study to prospectively evaluate the safety and efficacy of an IV iron replacement therapy (ferric carboxymaltose (FCM; Injectafer), as monotherapy for patients with CIA.
Design/Methods : This 18-week, double-blind, phase 3 study included adults &gt;18 years of age with CIA receiving chemotherapy (≥4 weeks' treatment remaining) for a non-myeloid malignancy. Inclusion criteria included: (Hb) 8-11 g/dL, ferritin 100-800 ng/mL, and transferrin saturation (TSAT) ≤35%; an Eastern Cooperative Oncology Group Performance Status [ECOG PS] score of 0-2; and life expectancy ≥6 months.
PwC were excluded if they received oral or IV iron, RBC transfusion, or ESAs within 4 weeks of screening; iron-containing multivitamins were permitted. Study patients were randomized 1:1 to receive IV FCM or IV placebo. FCM was administered as two 15-minute infusions each separated by 7 days, each at a dose of 15 mg/kg (maximum single dose: 750 mg [total dose ≤1500 mg] diluted in ≤250 mL saline). For blinding purposes, placebo was normal saline ≤250 mL, administered as covered 15-minute infusions. Patients were randomized 1:1 to receive FCM or placebo. The primary efficacy endpoint was percentage of patients with a decrease in Hb ≥0.5 g/dL from weeks 3 to 18; the secondary efficacy endpoint was change in Hb from baseline to end of treatment. Based on the assumption that 65% of patients in the placebo group and 42% of patients in the FCM group would not maintain baseline Hb concentrations, it was determined that 106 PwC were needed in each treatment group to provide 90% power to detect a statistically significant difference in the primary endpoint measured using a continuity-corrected 2-sided chi-squared test at a significance level of α=0.05.
Results: The study randomized 244 PwC (n=122, both groups). The percentage of patients with a decrease in Hb ≥0.5 g/dL from weeks 3 to 18 was significantly lower with FCM versus placebo (35.3% vs 50.8%; odds ratio=0.51, P=0.01). Improvements from baseline Hb to end of treatment were not significantly different between FCM and placebo (1.04 vs 0.87 g/dL), but were greater with FCM in a subgroup of patients with baseline Hb &lt;10 g/dL (P=0.01). The percentage of patients in the subgroup had an increase from baseline Hb of ≥1 g/dL (71% vs 54%, respectively; P=0.01) and a shorter median time to Hb increase of ≥1 g/dL (43 vs 85 days; P=0.001) versus placebo. The most common adverse events (AEs) were neutropenia (17% vs 12%), hypophosphatemia (16% vs 3%), and fatigue (15% vs 14%; FCM vs. placebo, respectively). VTE did not occur in any PwC in either arm. In general, FCM raised no safety signals and was well tolerated, with no notable difference between groups in the incidence of AEs other than hypophosphatemia. A decrease in serum phosphate (ie &lt; 2.0 mg/dL) from Day 7 to Week 3 was seen in up to 38% of patients receiving FCM, however this did not produce any symptoms in affected patients. No differences were found between the FCM and placebo groups who received non-study interventions (22 [18%] vs 25 [21%], respectively), including those requiring blood transfusions (15 [13%] vs 14 [12%]).
Conclusion: In this phase 3 trial of patients with CIA, Hb was maintained within ≥0.5 g/dL of baseline from weeks 3 to 18 in patients in 64.7% receiving FCM and 49.2% receiving placebo. Additionally, FCM maintained Hb for up to 18 weeks for the majority of PwC and CIA, and did not increase the risk for VTE.

Disclosures
Boccia: AMAG: Consultancy; AstraZeneca: Speakers Bureau; Amgen: Speakers Bureau; Celgene: Speakers Bureau; DSI: Speakers Bureau; Genentech: Speakers Bureau. Krupa:American Regent: Employment.

OffLabel Disclosure:
Unsure: This study discusses parenteral iron for chemotherapy-induced anemia. Currently, no IV iron product has a labeled indication for this specific patient population, however ferric carboxymaltose is indicated for adults who have intolerance to oral iron or have had unsatisfactory response to oral iron or adults who have non-dialysis dependent chronic kidney disease.