Dose Escalation Study of HBI-8000 in Combination With Paclitaxel and Trastuzumab in Women With Advanced or Metastatic HER2+ Breast Cancer

This is a phase I multi-center dose escalation study of the histone deacetylase inhibitor (HDACi) HBI-8000 when given in combination with paclitaxel and trastuzumab in women with advanced or metastatic HER2+ breast cancer. Three dose levels of HBI-8000 (15 mg, 20 mg, and 25 mg) will be tested using a standard 3+3 escalation plan with an expanded cohort at the maximum tolerated dose (MTD) to enroll a minimum of 10 patients evaluable for safety to fulfill the requirements for moving the combination forward to I-SPY 2 trial. To be considered evaluable for safety, the patient must receive at least 75% of their prescribed regimen per cycle for 4 consecutive cycles with a cycle of therapy defined as 28 days in the absence of disease progression or unacceptable toxicity. Patients who progress at 9 weeks evaluation or later but before completing 4 cycles and who have only experienced Grade ≤ 1 toxicities (excluding alopecia) will also be considered evaluable for safety. Enrolled patients will remain on their assigned dose level until unacceptable toxicity or disease progression occurs. During dose escalation phase, if more than 34% of the evaluable patients at a dose level experience dose limiting toxicities (DLT), this dose level will be considered having exceeded MTD. Once MTD is identified during dose escalation phase, the MTD dose level will be expanded in the expansion phase to enroll additional patients to ensure that at least 10 patients are evaluable for safety at the MTD. Paclitaxel and trastuzumab are administered by intravenous (IV) infusion on days 1, 8, 15, and 22 of a 28-day cycle. HBI-8000 will be taken by mouth twice weekly at the assigned dose on days 1, 4, 8, 11, 15, 18, 22 and 25 of a 28-day cycle. Treatment continues until disease progression, unacceptable toxicity, or patient refusal/non-compliance is observed. The study will evaluate the safety and tolerability of oral HBI-8000 bi-weekly in combination with weekly paclitaxel and trastuzumab and if successful, determine an optimal dose to move into phase II testing of this combination in the I-SPY 2 trial in a neo-adjuvant breast cancer population. To determine the MTD of HBI-8000 twice weekly in combination with weekly paclitaxel and trastuzumab in women with HER2+ breast cancer. * To determine the adverse event rate of twice weekly HBI-8000 in combination with weekly paclitaxel and trastuzumab * To determine the tolerability of twice weekly HBI-8000 when administered with weekly paclitaxel and trastuzumab * To explore efficacy of twice weekly HBI-8000 in combination with weekly paclitaxel and trastuzumab * To obtain pharmacokinetics of twice weekly HBI-8000 when administered in combination with weekly paclitaxel and trastuzumab. * To determine the on-target effect of HBI-8000 by measuring protein acetylation * To explore the treatment effects on immune cells in blood and/or tumor tissue as appropriate Enrolled patients will take HBI-8000 at the assigned dose twice weekly while receiving weekly paclitaxel and trastuzumab for a minimum of 8 weeks (2 treatment cycles). On the day of paclitaxel infusion, HBI-8000 is taken at least one hour before paclitaxel infusion. HBI-8000 should be taken within 30 minutes after a meal. The interval between HBI-8000 administrations is 3-4 days in the absence of dose delay or interruptions due to adverse events. For example, three days should elapse between the 1st and 2nd dose of HBI-8000 of the week, such as Monday/Thursday; Tuesday/Friday. A disease re-evaluation will be scheduled every 8 weeks. Based on the Response Evaluation Criteria in Solid Tumors 1.1 (RECIST1.1), response to treatment will be determined. Patients with stable disease (SD), partial response (PR) or complete response (CR) may continue treatment until disease progression, unacceptable side effects, or patient refusal/non-compliance occurs. Patients will be monitored in clinic every 4 weeks while receiving study treatment. The end of treatment (EOT) visit will occur at 4 weeks after the last dose of HBI-8000, or before the start of a new anti-cancer therapy, whichever is earlier. At EOT, patients will be evaluated for resolution of treatment related toxicities. Toxicity related to HBI-8000, if not yet resolved to Grade ≤ 1, will be followed until resolution to Grade ≤ 1 or considered chronic. All patients will be followed up to 1 year from study enrollment for best objective response, duration of response, time to PD, and survival.