A randomized, placebo-controlled phase 2 study of paclitaxel in combination with reparixin compared to paclitaxel alone as front-line therapy for metastatic triple-negative breast cancer (fRida)

Abstract

Purpose CXCR1, one of the receptors for CXCL8, has been identified as a druggable target on breast cancer cancer stem cells (CSC). Reparixin (R), an investigational oral inhibitor of CXCR1, was safely administered to metastatic breast cancer patients in combination with paclitaxel (P) and appeared to reduce CSC in a window-of-opportunity trial in operable breast cancer. The fRida trial (NCT02370238) evaluated the addition of R to weekly as first-line therapy for metastatic (m) TNBC. Subjects and Methods Subjects with untreated mTNBC were randomized 1:1 to R or placebo days 1–21 in combination with weekly P 80 mg/m2 on days 1, 8, 15 of 28-day cycles. The primary endpoint was PFS by central review. Results 123 subjects were randomized (62 to R + P and 61 to placebo + P). PFS was not different between the 2 groups (median 5.5 and 5.6 months for R + P and placebo + P, respectively; HR 1.13, p = 0.5996). ALDH+ and CD24−/CD44+ CSC centrally evaluated by IHC were found in 16 and 34 of the 54 subjects who provided a metastatic tissue biopsy at study entry. Serious adverse events (21.3 and 20% of subjects) and grade ≥ 3 adverse reactions (ADR) (9.1 and 6.3% of all ADRs) occurred at similar frequency in both groups. Conclusion fRida is the first randomized, double-blind clinical trial of a CSC-targeting agent in combination with chemotherapy in breast cancer. The primary endpoint of prolonged PFS was not met. Clinical Trial Registration/Date of Registration NCT01861054/February 24, 2015.

CXC Chemokine Signaling in Progression of Epithelial Ovarian Cancer: Theranostic Perspectives

“…In the clinical trials listed in Table 2 , there are four clinical trials for the combination of CXCR2 inhibitors and paclitaxel (NCT02583477, NCT02370238, NCT02001974, NCT01861054). Three of these trials used Reparicin (CXCR1/2 inhibitor) in combination with paclitaxel to treat patients with HER-2 negative metastatic breast cancer (MBC) and triple-negative breast cancer (TNBC), and the results of these clinical trials showed that the combination with Reparicin appeared to be safe and well-tolerated in patients (NCT02370238, NCT02001974, NCT01861054) [ 107 , 108 , 109 ]. However, the results of the clinical trial using another CXCR2 inhibitor, AZD5069, showed that all 23 patients in the trial experienced adverse events (AE), and 74% had AEs related to the treatment drug, so the trial was not completed (NCT02583477).…”

Are Cancer Stem Cells a Suitable Target for Breast Cancer Immunotherapy?

“…Besides mAb, small molecules have also been used to target the CSC/immune-microenvironment interaction and have reached the clinic; for example, ruxolitinib inhibits the IL-6/JAK/STAT pathway (NCT02066532, NCT02041429, NCT02876302, NCT02120417, NCT01562873, NCT01594216, NCT03012230) with evidence of clinical activity ( 24 ), while reparixin targets the IL-8 receptor CXCR1, selectively depletes CSCs in vitro and reduces tumor growth and metastasization in vivo ( 81 ). Reparixin has moved to clinical trials ( 83 ), giving promising results in terms of safety ( 84 ) and efficacy in reducing BCSC frequency ( 85 , 86 ). Other trials involving reparixin to target CSCs have been recently completed (NCT02370238, NCT02001974, NCT01861054).…”

Chemokines in the Landscape of Cancer Immunotherapy: How They and Their Receptors Can Be Used to Turn Cold Tumors into Hot Ones?

“…Along with this, Reparixin, a CXCR1 inhibitor, was effective in treating several NOD/SCID mice breast cancer models [ 146 ]. Currently, the extension of this study to human clinical trials is ongoing [ 153 ]. This therapy might be relevant to other cancers among them: gastric cancer [ 145 , 154 , 155 ], melanoma [ 156 , 157 , 158 , 159 , 160 , 161 , 162 , 163 , 164 , 165 ], and others.…”