HER2Pro 1B - Addition of prochlorperazine to paclitaxel, trastuzumab, and pertuzumab for previously untreated HER2-positive metastatic breast cancer: a phase 1 dose de-escalation study

Overview: Inhibition of dynamin-mediated endocytosis such as with prochlorperazine (PCZ) has been shown to increase the efficacy of trastuzumab and other monoclonal antibodies in preclinical models. Current standard therapy for metastatic HER2-positive breast cancer is paclitaxel in combination with trastuzumab and pertuzumab, followed by continuation of HER2-directed therapy until progression. The addition of PCZ has the potential for enhanced anticancer effect, but this novel combination needs to be assessed for feasibility and safety. Interventions: Standard treatment with paclitaxel 80mg/m2 weekly and loading dose trastuzumab 8mg/kg and pertuzumab 840mg. From cycle 2, paclitaxel 80mg/m2 weekly, trastuzumab 6mg/kg and pertuzumab 420mg every 3 weeks in combination with de-escalating doses of PCZ given as 6 weekly treatments. — Prochlorperazine Administration: Prochlorperazine will be administered as an intravenous infusion at a given dose level over 20 minutes, 60 minutes following the administration of cycle 2 of the standard treatment regimen of pertuzumab, trastuzumab and paclitaxel. The reason for this is that dexamethasone, which may impact ADCC, is not required from cycle 2 of the treatment. On completion of the prochlorperazine infusion, the intravenous line will be flushed with 100ml 0.9% normal saline. The standard reconstitution of prochlorperazine is within a solution of the mesylate salt in 5% dextrose. As the dose per infusion varies depending on body size and dose level, the concentration of the infusion will differ: for instance, an expected dose of prochlorperazine would be 50-100mg diluted in 250ml for a 1-2mg/5ml concentration solution running over 20 minutes. Prochlorperazine is given over 6 weeks, starting from day 1 of cycle 2. If there are no treatment associated serious adverse events, patient will continue for an additional 6 weeks of anti-cancer treatment and prochlorperazine. The procedure for these additional 6 weeks of therapy will be the same as described for Cycle 2 Day 1, however with only one blood test per week. — Dose limiting toxicity (DLT) and dose de-escalation: The DLT window will be 0-64 days following commencement of prochlorperazine at a given dose level. The first dose of study treatment for the first 2 patients treated at each dose level will be staggered by at least 24 hours. A patient will be considered evaluable for DLT if they have completed at least 1 infusion of prochlorperazine. Adverse events will be graded using CTCAE v5.0. Any DLT must be a toxicity that is considered related to the study drug prochlorperazine, including as a potential exacerbator of chemotherapy toxicity. The starting dose is DL1. If at any time, there are 2 or more DLTs at any given dose level, further accrual to that cohort will be ceased. Notice will be sent at re-initiation of accrual at the next lower dose. If the first 2 patients enrolled in DL-2 experience a DLT, the study will either cease or continue with an alternative treatment schedule. If more than 33% DLT evaluable patients in a DL cohort experience a DLT, further enrolment to that cohort will stop and a lower DL will be explored. If less than 33% DLT-evaluable patients in a DL cohort experience a DLT, the cohort will then be expanded to include 3 additional patients before the recommended phase 2 dose (RP2D) is declared, for additional safety exploration. The other medications pertuzumab, trastuzumab, and paclitaxel are given at the same dose regardless of prochlorperazine dose level. For the first cycle, these doses are pertuzumab 840 mg every 3 weeks, trastuzumab 8 mg/kg every 3 weeks, and paclitaxel 80 mg/m2 every week. For subsequent cycles, these doses are pertuzumab 420 mg every 3 weeks, trastuzumab 6 mg/kg every 3 weeks, and paclitaxel 80 mg/m2 every week. The RP2D will be the highest dose level achieved with prochlorperazine in combination with pertuzumab, trastuzumab, and paclitaxel where less than 33% patients enrolled have experienced a DLT. Assessment Plan: Clinical assessment Clinical assessment includes history, physical examination, and performance status. Participants will be reviewed by their study investigator weekly during the prochlorperazine infusions, then every 3 weeks. Subsequent clinical assessment frequency is at the discretion of the investigator. Imaging CT chest, abdomen, and pelvis, as well as 99mTc bone scan will be performed at screening, then at the safety visit (week 13 ± 3 days). Subsequent imaging frequency is at the discretion of the investigator. Blood collection Local pathology laboratories will be used for routine blood tests. Blood will be taken every week during the treatment period, then every 3 weeks, with additional assessments as clinically indicated. Subsequent standard-of-care blood test frequency will be at the discretion of the investigator. Translational blood tests are performed before and after each administration of prochlorperazine. Tissue collection Information and consent obtained if appropriate. If a biopsy hasn’t already been undertaken, a biopsy and 4ml blood plasma sample will be taken as part of standard care and transported straight to the laboratory for examination of immune status. If appropriate, biopsies may be taken under image guidance (ultrasound or computed tomography). Either that day or on the next available appointment (depending on patient availability) patient will be taken to the Oncology Day Unit where a Registered Nurse can monitor the patient and take blood samples. Here an intravenous line is inserted. This remains until the patient is discharged from the Oncology Day Unit. Subject receives 0.8mg/kg intravenous dose of prochlorperazine over 20-30 mins. A biopsy will be collected approximately 90 minutes post the administration of intravenous prochlorperazine. Patient will only be able to transfer from site if blood pressure is stable. They will be advised not to use machinery or drive for a further 24 hours. Transportation home will need to occur via a carer. Cardiac assessment Cardiac assessment with MUGA or echocardiogram should be performed during screening, then at the safety visit (cycle 5 or week 13 ± 3 days), then every 12 weeks subsequently, with other assessments as clinically indicated. Left ventricular ejection fraction (LVEF) assessment by echocardiography is preferred. The same method should be used throughout the study for each patient and preferably performed and assessed by the same assessor. An electrocardiogram (ECG) will be performed on initial screening visit, during each prochlorperazine infusion and at the end of treatment and 21-day safety assessment. End of treatment and 21-day safety assessment An end of treatment and safety assessment should be performed at 21 days after the last dose of study treatment to identify any adverse events occurring within this time. In the event of unresolved toxicity, participants should continue to be followed. Follow up after treatment Study-specific follow-up assessments after treatment should be completed at the specified time points (± 7 days). Subjects who stop study treatment prior to the time recommended in the protocol will continue follow-up visits according to the protocol. If a patient wishes to stop the study visits, they will be requested to allow their ongoing health status to be periodically reviewed via continued study visits or phone contact or from their general practitioner, or medical records, state-based cancer registries and/or the national mortality registry (AIHW). For patients who have been lost to follow-up, Medicare may be used to provide updated contact information and/or hospitalisations and the AIHW may be used to collect mortality information.