Abstract P2-09-15: A phase I study of interferon-gamma (γ)plus weekly paclitaxel, trastuzumab and pertuzumab in patients with HER-2 positive breast cancer
Authors: Han HS , Khong H , Costa R , Loftus L , Goodridge D , Henry T , Soliman H , Ismail-Khan R , Fridley B , Czerniecki B 
Published: May 2019

Abstract
Background: IFN-γ, a cytokine that plays diverse roles in innate and adaptive immunity, has been shown to be essential in anti-tumor immune response. In vitro and in vivo studies have shown the synergistic effect of IFN-γ in combination with HER2-targeting monoclonal antibodies with or without taxane chemotherapy. We have conducted a phase 1 clinical trial of systemic IFN-γ in combination with trastuzumab, pertuzumab, and paclitaxel in HER2-positive metastatic breast cancer.
Methods: Two dose levels (DL) of IFN-γ, 50 (DL1) and 75 mcg/m2 (DL2), were evaluated. IFN-γ was given as subcutaneous injection three times weekly starting on day 1 of therapy for 12 weeks. Paclitaxel was administered intravenously (IV) weekly at 80mg/m2 in combination with trastuzumab IV (8 mg/kg loading dose, then 6 mg/m2 q 21 days) and pertuzumab IV (840 mg loading dose, then 420 mg q 21 days). Eligible patients had measurable metastatic HER2-positive breast cancer, were candidates to receive paclitaxel chemotherapy, and had an ECOG PS 0-1. The primary objective of this study was to evaluate the safety and tolerability of the combination therapy during the 12 weeks of treatment and to determine the recommended phase II dose (RP2D). Dose-limiting toxicity (DLT) during cycle one was defined as follows: Non-hematologic or hematologic toxicities that are ≥ grade 3 and probably or definitely related to study therapy which lead to chemotherapy treatment delays &gt; 14 days.
Results: A total of nine patients (3 on DL1 and 6 on DL2) were enrolled between 2/2017 and 11/2017. No DLT was observed. For DL1, no serious adverse events (SAE) or significant adverse events (AE) were observed among 3 patients who completed 12 weeks of treatment. For DL2, two out of 6 patients had SAEs including grade 3 pneumonitis (at week 8; treatment was subsequently discontinued) and grade 3 non-neutropenic fever (at week 6), which were possibly related to study treatment. These toxicities, however, did not meet the protocol definition of DLT. Based on these findings suggesting an improved tolerability of DL1 (50 mcg/m2), DL1 was selected as the RP2D. The most frequently observed grade 1 and 2 AEs that were at least possibly related to IFN-γ were fatigue (45%) nausea (36%), myalgia (36%), and fever (27%) diarrhea (18%). No grade 4 AE was noted. Grade 3 AEs included diarrhea, nausea, pneumonitis, non-neutropenic fever. Three out of 9 patients achieved partial response and 6 patients had stable disease per RECIST criteria.
Conclusion: IFN-γ in combination with trastuzumab, pertuzumab, and paclitaxel was well tolerated in patients with HER2-positive metastatic breast cancer. Updated results will be presented and the phase 2 neoadjuvant trial is ongoing to further assess the efficacy of this approach.
Citation Format: Han HS, Khong H, Costa R, Loftus L, Goodridge D, Henry T, Soliman H, Ismail-Khan R, Fridley B, Czerniecki B. A phase I study of interferon-gamma (γ)plus weekly paclitaxel, trastuzumab and pertuzumab in patients with HER-2 positive breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-09-15.