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Phase Ib Pilot Study to Evaluate Reparixin in Combination with Weekly Paclitaxel in Patients with HER-2-Negative Metastatic Breast Cancer.

ABSTRACT: Purpose: Chemokine receptor 1 (CXCR1) is recognized as an actionable receptor selectively expressed by breast cancer stem cells (BCSCs). Reparixin is an investigational allosteric inhibitor of chemokine receptors 1 and 2 (CXCR1/2), and demonstrates activity against BCSCs in human breast cancer xenografts. This phase Ib clinical trial examined dose, safety, and pharmacokinetics of paclitaxel plus reparixin therapy, and explored effects of reparixin on BCSCs in patients with metastatic breast cancer (MBC) (trial registration ID: NCT02001974).Experimental Design: Eligible patients had MBC and were candidates for paclitaxel therapy. Study treatment included a 3-day run-in with reparixin oral tablets three times a day, followed by paclitaxel 80 mg/m2/week (days 1, 8, and 15 for 28-day cycle) + reparixin tablets three times a day for 21/28 days; three dose cohorts were examined in a 3+3 dose escalation schema. Additional patients were recruited into an expansion cohort at the recommended phase II dose to further explore pharmacokinetics, safety, and biological effects of the combination therapy.Results: There were neither G4-5 adverse events nor serious adverse events related to study therapy and no interactions between reparixin and paclitaxel to influence their respective pharmacokinetic profiles. A 30% response rate was recorded, with durable responses >12 months in two patients. Exploratory biomarker analysis was inconclusive for therapy effect on BCSCs.Conclusions: Weekly paclitaxel plus reparixin in MBC appeared to be safe and tolerable, with demonstrated responses in the enrolled population. Dose level 3, 1200 mg orally three times a day, was selected for further study in a randomized phase II trial (NCT02370238). Clin Cancer Res; 23(18); 5358-65. ©2017 AACR.

SUBMITTER: Schott AF

PROVIDER: S-EPMC5600824 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Phase Ib Pilot Study to Evaluate Reparixin in Combination with Weekly Paclitaxel in Patients with HER-2-Negative Metastatic Breast Cancer.

Schott Anne F AF Goldstein Lori J LJ Cristofanilli Massimo M Ruffini Pier Adelchi PA McCanna Susan S Reuben James M JM Perez Raymond P RP Kato Giraldo G Wicha Max M

Clinical cancer research : an official journal of the American Association for Cancer Research 20170524 18

<b>Purpose:</b> Chemokine receptor 1 (CXCR1) is recognized as an actionable receptor selectively expressed by breast cancer stem cells (BCSCs). Reparixin is an investigational allosteric inhibitor of chemokine receptors 1 and 2 (CXCR1/2), and demonstrates activity against BCSCs in human breast cancer xenografts. This phase Ib clinical trial examined dose, safety, and pharmacokinetics of paclitaxel plus reparixin therapy, and explored effects of reparixin on BCSCs in patients with metastatic brea ...[more]

PMID: 28539464

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Project description:BackgroundHeat shock protein 90 (HSP90) is a molecular chaperone required for stabilization of client proteins over-activated in triple-negative breast cancer (TNBC). Over-expression of HSP90 client proteins has been implicated in paclitaxel resistance. Onalespib (AT13387) is a potent inhibitor of HSP90 that could improve paclitaxel efficacy when administered in combination.DesignThis phase Ib trial administered onalespib with paclitaxel in patients with advanced TNBC to assess safety and establish a recommended phase II dose (RP2D).ObjectivesThe primary objectives were determining the dose-limiting toxicities and maximum tolerated dose of combination therapy. Secondary objectives included pharmacokinetic (PK) analysis and determination of overall response rate (ORR), duration of response (DOR), and progression-free survival (PFS).MethodsPatients with advanced TNBC were treated with standard dose intravenous paclitaxel in combination with intravenous onalespib at doses ranging from 120 to 260 mg/m2 administered on days 1, 8, and 15 of a 28-day cycle using a standard 3 + 3 design. A total of 15 patients were enrolled to dose expansion cohort at RP2D to confirm safety profile.ResultsThirty-one patients were enrolled in the study, of which over 90% had received prior taxane therapy. Paclitaxel was given for metastatic disease in 23% of patients. Adverse events (AEs) included anemia (grade 3: 20%), lymphopenia (grade 3: 17%), and neutropenia (grade 3: 33%, grade 4: 4%). The most frequent grade ⩾3 non-hematologic AE was diarrhea (7%). The established RP2D was 260 mg/m2 onalespib when given with paclitaxel at 80 mg/m2. PK analysis revealed a modest drug interaction profile for onalespib in the combination regimen. ORR was 20%. Three patients achieved complete responses, all of whom had received prior taxane therapy. Median DOR was 5.6 months; median PFS was 2.9 months.ConclusionCombination treatment with onalespib and paclitaxel had an acceptable toxicity profile and RP2D was determined to be 260 mg/m2 of onalespib. Combination therapy showed antitumor activity in patients with advanced TNBC.Trial registrationOnalespib and paclitaxel in treating patients with advanced TNBC https://clinicaltrials.gov/ct2/show/NCT02474173.

Project description:BackgroundStrategies to improve activity of immune checkpoint inhibitors for triple-negative breast cancer (TNBC) are needed. Preclinical studies showed that antiangiogenic agents and poly (ADP-ribose) polymerase (PARP) inhibitors might sensitize tumors to immunotherapy. Here, we investigated the tolerability, safety, and preliminary antitumor activity of camrelizumab, an anti-PD-1 antibody, in combination with apatinib, a vascular endothelial growth factor receptor-2 inhibitor, and fuzuloparib, a PARP inhibitor, in patients with recurrent or metastatic TNBC.MethodsThis phase Ib study included a dose-finding part and a dose-expansion part. In the dose-finding part, a 3 + 3 dose escalation scheme was introduced. Patients were given camrelizumab (200 mg every 2 weeks) plus apatinib (375 mg or 500 mg once daily) and fuzuloparib (starting dose 100 mg twice daily) every 28-day cycle. After evaluation of the tolerability and safety of the dosing regimens, a clinical recommended dose was determined for the dose-expansion part. The primary endpoint was dose-limiting toxicity (DLT).ResultsA total of 32 patients were enrolled. Three patients received camrelizumab 200 mg + apatinib 375 mg + fuzuloparib 100 mg, and 29 received camrelizumab 200 mg + apatinib 500 mg + fuzuloparib 100 mg (clinical recommended dose). No DLTs were observed in either group. The most common grade ≥ 3 treatment-related adverse events were decreased white blood cell count (20.7%), hypertension (13.8%), decreased neutrophil count (10.3%), and increased aspartate aminotransferase (10.3%). Two patients discontinued study treatment due to immune-mediated hepatitis (n = 1) and anemia, decreased platelet count, decreased white blood cell count, increased alanine aminotransferase, increased aspartate aminotransferase, and increased γ-glutamyltransferase (n = 1). One patient died of unknown cause. Two (6.9% [95% CI, 0.9-22.8]) of 29 patients with camrelizumab 200 mg + apatinib 500 mg + fuzuloparib 100 mg had objective response. The disease control rate was 62.1% (95% CI, 42.3-79.3). The median progression-free survival was 5.2 months (95% CI, 3.6-7.3), and the 12-month overall survival rate was 64.2% (95% CI, 19.0-88.8).ConclusionsCombination of camrelizumab plus apatinib and fuzuloparib showed manageable safety profile and preliminary antitumor activity in patients with recurrent or metastatic TNBC.Trial registrationClinicalTrials.gov NCT03945604 (May 10, 2019).

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Phase Ib Pilot Study to Evaluate Reparixin in Combination with Weekly Paclitaxel in Patients with HER-2-Negative Metastatic Breast Cancer.

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Phase Ib Pilot Study to Evaluate Reparixin in Combination with Weekly Paclitaxel in Patients with HER-2-Negative Metastatic Breast Cancer.

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