Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622000016730
Ethics application status
Approved
Date submitted
12/10/2021
Date registered
11/01/2022
Date last updated
23/06/2024
Date data sharing statement initially provided
11/01/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
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
Scientific title
Addition of prochlorperazine to paclitaxel, trastuzumab, and pertuzumab for previously untreated HER2-positive metastatic breast cancer: a phase 1 dose de-escalation study
Secondary ID [1] 305532 0
None
Universal Trial Number (UTN)
Trial acronym
HER2Pro 1B
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Metastatic HER2-positive breast cancer 323920 0
Condition category
Condition code
Cancer 321434 321434 0 0
Breast

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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.
Intervention code [1] 321928 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 329214 0
The primary objective is to determine the recommended phase 2 dose (RP2D), defined as the highest dose level achieved with prochlorperazine in combination with pertuzumab, trastuzumab, and paclitaxel where less than 33% patients enrolled have experienced a dose limiting toxicity (DLT).

Dose limiting toxicity assessed by the occurrence of treatment-emergent adverse events (TEAEs) graded by the Investigator per the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (NCI CTCAE v5.0)

Patients will be assessed for the presence of a DLT during their routine clinical assessments. which includes history, physical examination, and performance status, as well as at the end of their treatment and safety assessment.
Timepoint [1] 329214 0
Clinical assessments - 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.

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.
Secondary outcome [1] 401797 0
Frequency and severity of adverse events (CTCAE v5.0)

The CTCAE v5.0 will be used to classify and grade the intensity of adverse events observed during the study period.
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. For this study, DLTs are defined as:
Haematologic dose limiting toxicity
- Grade 4 neutropenia lasting > 5 days
- Febrile neutropenia lasting > 48 hours or associated with haemodynamic compromise or objective evidence of infection
- Grade 4 thrombocytopenia of any duration
- Greater than or equal to Grade 3 thrombocytopenia associated with clinically significant bleeding

Non-haematologic dose limiting toxicity
- Greater than or equal to Grade 3 ALT or AST rise, greater than or equal to Grade 3 bilirubin rise, or likely drug-induced liver injury per Hy’s law, defined as all of:
-- ALT or AST - Greater than or equal to 3x ULN; and
-- Total bilirubin - Greater than or equal to 2x ULN; and
-- No alternative aetiology can be identified.
- Grade 3 syncope or greater than or equal to Grade 3 hypotension.
- Greater than or equal to grade 3 constipation, only if not resolving to lesser than or equal to Grade 1 within 14 days with medical therapy.
- Greater than or equal to Grade 2 urinary retention.
- Greater than or equal to Grade 3 fatigue lasting > 7 days.
- Greater than or equal to Grade 3 cardiac arrhythmia, including Torsades de Pointes.
- Greater than or equal to Grade 3 psychosis.
- Greater than or equal to Grade 3 extrapyramidal disorder lasting > 5 days, such as acute dystonia including oculogyric crisis, tardive dyskinesia, torticollis, akathisia.
Timepoint [1] 401797 0
Clinical assessments - 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.

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.
Secondary outcome [2] 401798 0
Rate of reduction in LVEF

Rate of reduction in left ventricular ejection fraction (LVEF) is defined as the proportion of participants with reduction in LVEF, defined as an absolute fall of at least 10% from baseline to a new LVEF of less than 50%.

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.
Timepoint [2] 401798 0
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.
Secondary outcome [3] 401799 0
Objective response rate (ORR, RECIST 1.1)

Objective response rate (ORR) is defined as the proportion of participants with objective response, defined as a complete response (CR) or partial response (PR) according to RECIST v1.1 recorded from enrolment until disease progression or death due to any cause. Patients not recording CR or PR and patients with inadequate data for tumour assessment are considered non-responders in the ORR analysis.
Timepoint [3] 401799 0
An end of treatment and safety assessment should be performed at 21 days after the last dose of study treatment.
Secondary outcome [4] 401800 0
Duration of response (DOR, RECIST 1.1)

Duration of response (DOR) is defined as the time from the first documentation of objective response (CR or PR) to the first documentation of objective tumour progression or death due to any cause, whichever occurs first.
Timepoint [4] 401800 0
An end of treatment and safety assessment should be performed at 21 days after the last dose of study treatment.

DOR data will be censored on the date of the last tumour assessment on study for patients who do not have objective tumour progression and who do not die due to any cause while on study. DOR will only be calculated for the subgroup of patients with an objective response.
Secondary outcome [5] 401801 0
Progression-free survival (PFS, RECIST 1.1)

Progression-free survival (PFS) is defined as the time from enrolment to the date of the first documentation of progression of disease (PD) or death due to any cause in the absence of documented PD, whichever occurs first.
Timepoint [5] 401801 0
An end of treatment and safety assessment should be performed at 21 days after the last dose of study treatment.

PFS data will be censored on the date of the last tumour assessment on study for patients who do not have objective tumour progression and who do not die due to any cause while on study. Participants lacking an evaluation of tumour response after enrolment will have their PFS time censored on the date of enrolment with the duration of one day.

Eligibility
Key inclusion criteria
Patients with previously untreated HER2-positive locally advanced or metastatic breast cancer who are suitable for treatment with the combination of prochlorperazine and standard systemic therapy with paclitaxel, pertuzumab, and trastuzumab systemic therapy.
Minimum age
18 Years
Maximum age
No limit
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
- History of anticancer therapy for advanced breast cancer with the possible exception of one prior endocrine therapy regimen (such as an aromatase inhibitor or tamoxifen, with or without goserelin).
- History of exposure to the following cumulative doses of anthracyclines: Doxorubicin or liposomal doxorubicin > 360 mg/m2; Epirubicin > 720 mg/m2
- Peripheral neuropathy of greater than or equal to Grade 2 at baseline by CTCAE v5.0.
- Prior radiotherapy or surgery within 14 days of study registration.
- Unwilling to avoid driving or operating machinery for up to 24 hours after administration of study medication.
- Current chronic daily treatment with corticosteroids at a dose > 10mg/day prednisolone equivalent, excluding inhaled steroids.
- Known hypersensitivity or prior intolerable adverse reaction to prochlorperazine, paclitaxel, trastuzumab, or pertuzumab.
- Systolic blood pressure < 90 mmHg and/or diastolic blood pressure < 50 mmHg in two consecutive blood pressure readings within the 1 hour prior to study drug administration.
- Parkinson disease or other chronic extrapyramidal condition.
- Clinically significant cardiovascular disease less than or equal to 1 year prior to enrolment, including myocardial infarction, unstable angina, symptomatic congestive heart failure, and/or serious uncontrolled cardiac arrhythmia.
- History of prolonged QT interval, QTcF > 450ms on baseline ECG, and/or taking medications or supplements with a known risk of prolonging the QT interval or inducing Torsades de Pointes.
- History of interstitial lung disease, such as pneumonitis or pulmonary fibrosis or evidence of interstitial lung disease on previous imaging.
- Significant prior or concurrent malignancy. Note that malignancies with very low risk of interfering with either participation or endpoint interpretation are permitted, such as adequately treated carcinoma-in-situ of the cervix, or basal cell or squamous cell carcinoma of the skin.
- Pregnant or lactating women.
- Serious medical or psychiatric condition that might limit the ability of the patient to consent to the study and/or comply with the protocol.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis
The sample size will be between 6 and 12 patients based on a 3+3 dose de-escalation design.

Safety analyses will include all participants who received at least one dose of study treatment.
Efficacy analyses will be by intention-to-treat and include all participants recruited, regardless of whether they received study treatment.
Time to event data will be summarised using the Kaplan Meier method including all participants recruited.
Measures of effect will be reported with 2-sided 95% confidence intervals calculated with appropriate methods.
Suitable regression models will be used to test the effects of baseline characteristics on key endpoints, e.g. PSA response, pain response, etc. Logistic regression will be used for dichotomous endpoints. Cox proportional hazards models will be used for time-to-event endpoints. Linear regression will be used for HRQL data, using models for repeated measures data as appropriate.
Sensitivity analyses will be used to assess effects on the findings and conclusions of excluding participants who were deemed ineligible, unevaluable, or did not receive study treatment.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/03/2022
Actual
20/06/2023
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
12
Accrual to date
3
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD
Recruitment hospital [1] 20720 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [2] 20721 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment postcode(s) [1] 35525 0
2010 - Darlinghurst
Recruitment postcode(s) [2] 35524 0
4102 - Woolloongabba

Funding & Sponsors
Funding source category [1] 309901 0
Government body
Name [1] 309901 0
NHMRC Ideas Grant
Country [1] 309901 0
Australia
Primary sponsor type
University
Name
University of Queensland
Address
The University of Queensland
St Lucia, QLD 4072
Country
Australia
Secondary sponsor category [1] 310930 0
None
Name [1] 310930 0
Nil
Address [1] 310930 0
Nil
Country [1] 310930 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309623 0
Metro South Human Research Ethics Committee
Ethics committee address [1] 309623 0
Level 7, Translational Research Institute Building
Princess Alexandra Hospital
Ipswich Road, Woolloongabba Qld 4102
Ethics committee country [1] 309623 0
Australia
Date submitted for ethics approval [1] 309623 0
04/05/2021
Approval date [1] 309623 0
13/10/2021
Ethics approval number [1] 309623 0
HREC /2021/QMS/73121

Summary
Brief summary
The purpose of this study is to determine the safety and efficacy of the addition of an anti-nausea drug called prochlorperazine to current standard of care treatment for patients with HER2-positive breast cancer.

By administering a high dose of prochlorperazine as an infusion directly into your veins over a short period of time (20-30 minutes), the process by which cells absorb molecules may be blocked. When this absorption process is blocked, it is thought that individuals may respond better to one of the drugs used to treat HER2-positive breast cancer.

Who is it for?
You may be eligible for this study if you are an adult who has metastatic HER2-positive breast cancer and you haven’t chemotherapy treatment yet.

Study details
All patients in this study will receive a high dose of prochlorperazine 3 weeks after the commencement of their chemotherapy. After this, all patients will receive the prochlorperazine weekly with their usual chemotherapy. There will be different doses of the prochlorperazine given to participants depending on when the participant joins the study, with the doses starting at the highest dose and then decreasing over time dependent upon any safety concerns.

It is hoped that this research will help determine if the high dose prochlorperazine is safe in combination with chemotherapy to treat patients with HER2-postive breast cancer, while also testing whether this has an effect on improving health outcomes.
Trial website
Trial related presentations / publications
Public notes
Joseph SR, Gaffney D, Barry R, Hu L, Banushi B, Wells JW, et al. An ex vivo human tumor assay shows distinct patterns of EGFR trafficking in squamous cell carcinoma correlating to therapeutic outcomes. J Invest Dermatol. 2019;139(1):213-23.

Chew HY, De Lima PO, Cruz JLG, Banushi B, Echejoh G, Hu L, et al. Endocytosis inhibition in humans to improve responses to ADCC-mediating antibodies. Cell. 2020;180(5):895-914. e27.

Boero S, Morabito A, Banelli B, Cardinali B, Dozin B, Lunardi G, et al. Analysis of in vitro ADCC and clinical response to trastuzumab: possible relevance of Fc gamma RIIIA/Fc famma RIIA gene polymorphisms and HER-2 expression levels on breast cancer cell lines. J Transl Med. 2015;13(1):324.

Joseph SR, Lum B, Banushi B, Barry R, Panizza B, Walpole E, et al. Antibody/Ligand-Target Receptor Internalization Assay Protocol Using Fresh Human or Murine Tumor Ex Vivo Samples. STAR Protoc. 2020;1(2):100087.

Contacts
Principal investigator
Name 114810 0
Prof Elgene Lim
Address 114810 0
St Vincent’s Hospital
Medical Oncology 406 Victoria Street
Darlinghurst Sydney NSW 2010
Country 114810 0
Australia
Phone 114810 0
+61 2 9355 5823
Fax 114810 0
Email 114810 0
e.lim@garvan.org.au
Contact person for public queries
Name 114811 0
Prof Euan Walpole
Address 114811 0
Princess Alexandra Hospital
199 Ipswich Rd, Woolloongabba QLD 4102
Country 114811 0
Australia
Phone 114811 0
+61 3176 2111
Fax 114811 0
Email 114811 0
Euan.Walpole@health.qld.gov.au
Contact person for scientific queries
Name 114812 0
A/Prof Fiona Simpson
Address 114812 0
The University of Queensland Diamantina Institute
Level 7, 37 Kent St
Translational Research Institute (TRI)
Woolloongabba, QLD 4102
Australia
Country 114812 0
Australia
Phone 114812 0
+61 422721656
Fax 114812 0
Email 114812 0
f.simpson@uq.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
De-identified safety data for progression to Phase II trials
When will data be available (start and end dates)?
From end of study; no end date to data availability
Available to whom?
Public access - de-identified data
Available for what types of analyses?
Analysis of safety for progression to efficacy trials
How or where can data be obtained?
Will be published in scientific literature and database supplied open access


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
13525Study protocol    382938-(Uploaded-02-11-2021-09-50-25)-Study-related document.pdf
13526Informed consent form    382938-(Uploaded-12-10-2021-16-18-46)-Study-related document.pdf



Results publications and other study-related documents

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