Phase I study of JAK1/2 inhibitor ruxolitinib with weekly paclitaxel for the treatment of HER2-negative metastatic breast cancer

Abstract

Purpose

Preclinical studies support the JAK2–STAT3 signaling pathway as a key driver in CD44+ CD24− “stem-cell-like” breast cancer cells. Ruxolitinib is an orally bioavailable JAK1/2 inhibitor. We aimed to identify the recommended phase 2 dose (RP2D) of ruxolitinib in combination with paclitaxel in patients with HER2-negative metastatic breast cancer (MBC).

Methods

Eligible patients had HER2-negative MBC and had received ≤ 3 chemotherapy regimens for advanced disease. Patients received oral ruxolitinib (10–25 mg bid) in a 3 + 3 dose escalation design in combination with weekly paclitaxel 80 mg/m2 in a 3-week cycle. The primary objective was to determine the maximum tolerated dose (MTD) and the RP2D.

Results

Nineteen patients received protocol therapy (mean age 52 years). Eight (42%) had triple-negative breast cancer and 11 (58%) had hormone receptor-positive disease; 12 (63%) had visceral disease. Ten (53%) patients had not received prior treatment for advanced disease. Patients received a median number of 5 cycles of combination therapy (range 1–12) and five patients continued single-agent ruxolitinib. The MTD of ruxolitinib was 25 mg bid when combined with paclitaxel, and the RP2D for the combination was 15 mg bid. Thirteen (68%) patients required dose reductions or holds. Most frequent toxicities reported of any grade were neutropenia (50%) and anemia (33%). There were no grade 4/5 toxicities attributed to study drug. Four (21%) patients had PR, 12 (63%) had SD and three (16%) had PD as their best response.

Conclusion

The combination of ruxolitinib and weekly paclitaxel was well tolerated with evidence of clinical activity. Further analysis of this combination is ongoing (NCT02041429).

Trial registration

NCT02041429. Date of registration: January 22, 2014.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Code availability

Not applicable.

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Funding

Incyte Corporation, Alapocas, Delaware.

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Authors

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Correspondence to Filipa Lynce.

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Conflicts of interest

FL has received research grants from Pfizer, Immunomedics, Regeneron, Chugai, Tesaro, Calithera, Inivata and BMS and has participated on advisory boards from Pfizer (remunerated) and BMS, Astra Zeneca and Jounce (non remunerated). BO has received clinical trial support from Incyte, Eisai. SMT receives institutional research funding from AstraZeneca, Lilly, Merck, Nektar, Novartis, Pfizer, Genentech/Roche, Immunomedics, Exelixis, Bristol-Myers Squibb, Eisai, Nanostring, Cyclacel, Odonate, and Seattle Genetics; has served as an advisor/consultant to AstraZeneca, Lilly, Merck, Nektar, Novartis, Pfizer, Genentech/Roche, Immunomedics, Bristol-Myers Squibb, Eisai, Nanostring, Puma, Sanofi, Celldex, Paxman, Puma, Silverback Therapeutics, G1 Therapeutics, AbbVie, Anthenex, OncoPep, Outcomes4Me, Kyowa Kirin Pharmaceuticals, Daiichi-Sankyo, and Samsung Bioepsis Inc. RAF receives institutional funding from Eisai and Puma Biotechnology. ELM has served as a consultant/advisor to Novartis, Lilly, Sanofi, and Eisai. MMR reports research funding from Novartis, Pfizer, Ipsen, TerSera, Merck, Pierre Fabre, Roche, AstraZeneca, Bristol Myers Squibb, Bayer, Veridex; and consulting or advisory role for Ipsen, Bristol-Myers Squibb, Tolmar Pharmaceuticals.

Ethics approval

This study was approved by the Dana-Farber/Harvard Cancer Center Institutional Review Board (DFCI#13–494; NCT02041429).

Consent to participate

Informed consent was obtained from all subjects.

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Not applicable.

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Prior presentation: San Antonio Breast Cancer Symposium 2016 (Overmoyer B, Regan M et al. Abstract P6-12-12: Phase I study of the JAK1/2 inhibitor ruxolitinib with weekly paclitaxel for the treatment of HER2 negative metastatic breast cancer (MBC). Cancer Res 2017; 77(4 Supplement): P6-12-12.

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Lynce, F., Williams, J.T., Regan, M.M. et al. Phase I study of JAK1/2 inhibitor ruxolitinib with weekly paclitaxel for the treatment of HER2-negative metastatic breast cancer. Cancer Chemother Pharmacol 87, 673–679 (2021). https://doi.org/10.1007/s00280-021-04245-x

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Keywords

  • Ruxolitinib
  • Paclitaxel
  • Phase I study
  • Metastatic breast cancer
  • JAK1/2