A Phase 1b, Open-label Study to Assess the Safety and Tolerability of Tucatinib (ONT-380) Combined With Capecitabine and Trastuzumab, Alone and in Combination in HER2+ Metastatic Breast Cancer

Brief Summary

Detailed Description

This is a study of tucatinib (ONT-380) given in combination with capecitabine alone, trastuzumab alone and with both capecitabine and trastuzumab in patients with HER2+ metastatic breast cancer. This study will use a 3+3 dose escalation design to evaluate escalating dose levels of tucatinib (ONT-380) in each of these three combinations in order to identify the maximal tolerated dose/recommended phase 2 dose (MTD/RP2D) of tucatinib (ONT-380). The MTD/RP2D of tucatinib (ONT-380) to be used in combination with either capecitabine alone (Combination 1) or trastuzumab alone (Combination 2) will be determined prior to evaluating tucatinib (ONT-380) in combination with both capecitabine and trastuzumab (Combination 3). If Combination 1 and Combination 2 are found to be tolerable, then tucatinib (ONT-380) will be evaluated in Combination 3, using the lowest MTD/RP2D or other SMC-recommended dose of tucatinib (ONT-380) determined for either of the two drug combinations. This will be followed by enrollment of an expansion cohort of patients treated at the MTD/RP2D for Combination 3. Additional expansion cohorts for either Combination 1 (tucatinib (ONT-380) and capecitabine) or Combination 2 (tucatinib (ONT-380) and trastuzumab) may also be enrolled. Capecitabine will be given twice per day orally at 1000 mg/m\^2 on Days 1-14 of each 21-day cycle. Trastuzumab will be given as a loading dose of 8 mg/kg IV followed by 6 mg/kg once every 21 days. However, a loading dose of trastuzumab will not be given to patients who have received trastuzumab within 4 weeks of the first study dose of trastuzumab. These patients will receive trastuzumab at 6 mg/kg each cycle, including Cycle 1. Trastuzumab may also be given on a weekly basis at 2 mg/kg IV q 7 days, but only in the circumstance that trastuzumab infusion has been delayed, and weekly infusions are required to resynchronize the cycle length to 21 days, after discussion with the medical monitor. Trastuzumab infusion rates will be per institutional guidelines. Tucatinib (ONT-380) will be given twice per day orally at a dose dependent upon the dosing cohorts to which the patient is enrolled. There will be 3-6 evaluable patients enrolled in each cohort in the dose escalation phase, unless that dose is found to be intolerable prior to completion of enrollment. At least 6 evaluable patients are to be treated at a dose level in order for an MTD/RP2D to be determined. Provided that only seven dose cohorts are needed for dose escalation and only the expansion cohort for Combination 3 is enrolled, up to 66 evaluable patients may be enrolled. Additional patients may be enrolled if additional expansion cohorts are opened.

Primary Outcomes

Secondary Outcomes

• Duration of response(26 months)
• Incidence of clinical lab abnormalities (hematology, chemistry, liver function tests, coagulation, urinalysis)(Up to approximately 4 years)
• Severity of clinical lab abnormalities (hematology, chemistry, liver function tests, coagulation, urinalysis)(Up to approximately 4 years)
• Frequency of dose reductions in tucatinib (ONT-380(Up to approximately 4 years)
• Frequency of dose reductions in capecitabine(Up to approximately 4 years)
• Plasma concentrations of tucatinib (ONT-380) and metabolite(26 months)
• Plasma concentrations of capecitabine and metabolites(26 months)
• Objective response rate (ORR)(26 months)
• Disease control rate(26 months)
• Clinical benefit rate (CBR)(26 months)
• Progression-free survival (PFS)(Up to 6 years)