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Trial registered on ANZCTR


Registration number
ACTRN12624001340527
Ethics application status
Approved
Date submitted
26/09/2024
Date registered
5/11/2024
Date last updated
5/11/2024
Date data sharing statement initially provided
5/11/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
Paxalisib Plus Olaparib or Pembrolizumab/Chemotherapy in Advanced Breast Cancer
Scientific title
A Phase 1b, Multi-centre, Open-label, Randomized Study to Evaluate the Safety, Tolerability, and Clinical Activity of Combining Paxalisib with Olaparib or Pembrolizumab/Chemotherapy in Patients with Advanced Breast Cancer
Secondary ID [1] 313014 0
KZA-0084-ABC001
Universal Trial Number (UTN)
Trial acronym
PaxPlus-ABC
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Breast cancer 335212 0
Condition category
Condition code
Cancer 331764 331764 0 0
Breast

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Arm A, Cohort 1: Paxalisib 15 mg plus Olaparib Participants will receive paxalisib 15 mg (1 x 15 mg capsule) administered orally once daily with Olaparib 300 mg (2x 150 mg tablets) orally twice daily in 28 day cycles. Treatment may be continued for up to 12 months. There is no rest period between each cycle. Dose interruptions are permitted in the case of medical or surgical events or logistical reasons not related to study therapy (e.g. elective surgery, unrelated medical events, inclement weather, etc.). Participants are required to resume therapy within 4 weeks.

Arm A, Cohort 2: Paxalisib 30 mg plus Olaparib Participants will receive paxalisib 30 mg (2 x 15 mg capsule) administered orally once daily with Olaparib 300 mg (2x 150 mg tablets) orally twice daily in 28 day cycles. Treatment may be continued for up to 12 months. There is no rest period between each cycle. Dose interruptions are permitted in the case of medical or surgical events or logistical reasons not related to study therapy (e.g. elective surgery, unrelated medical events, inclement weather, etc.). Participants are required to resume therapy within 4 weeks.

In ARM A adherence to Paxalisib and Olaparib dosing will be monitored via bottle returns.

Arm B, Cohort 1: Paxalisib 15 mg plus pembrolizumab/chemotherapy Participants will receive paxalisib 15 mg (1 x 15 mg capsule) administered orally once daily in 21 day cycles. Pembrolizumab 200 mg (100 mg/4 mL) intravenous infusion will be administered on Day 1 of each 21 day cycle together with chemotherapy (intravenous nanoparticle albumin-bound paclitaxel, or gemcitabine–carboplatin) administered per standard of care protocol. Treatment may be continued for up to 12 months. There is no rest period between each cycle. Dose interruptions are permitted in the case of medical or surgical events or logistical reasons not related to study therapy (e.g. elective surgery, unrelated medical events, inclement weather, etc.). Participants are required to resume therapy within 4 weeks.

Arm B, Cohort 2: Paxalisib 30 mg plus pembrolizumab/chemotherapy Participants will receive paxalisib 30 mg (2 x 15 mg capsule) administered orally once daily in 21 day cycles. Pembrolizumab 200 mg (100 mg/4 mL) intravenous infusion will be administered on Day 1 of each 21 day cycle together with chemotherapy (intravenous nanoparticle albumin-bound paclitaxel, or gemcitabine–carboplatin) administered per standard of care protocol. Treatment may be continued for up to 12 months. There is no rest period between each cycle. Dose interruptions are permitted in the case of medical or surgical events or logistical reasons not related to study therapy (e.g. elective surgery, unrelated medical events, inclement weather, etc.). Participants are required to resume therapy within 4 weeks.

In ARM B Adherence to Paxalisib dosing will be monitored via bottle returns and adherence to Pembrolizumab/chemotherapy will be confirmed by the site staff when participants receive their dose at site.
Intervention code [1] 329562 0
Treatment: Drugs
Comparator / control treatment
A dose comparison will be conducted between ARM A cohort 1 [paxalisib 15 mg (1 x 15 mg capsule) administered orally once daily with Olaparib 300 mg (2x 150 mg tablets) orally twice daily in 28 day cycles] and ARM A cohort 2 [paxalisib 30 mg (2 x 15 mg capsule) administered orally once daily with Olaparib 300 mg (2x 150 mg tablets) orally twice daily in 28 day cycles].

A dose comparison will be conducted between ARM B cohort 1 [ paxalisib 15 mg (1 x 15 mg capsule) administered orally once daily in 21 day cycles; pembrolizumab 200 mg (100 mg/4 mL) intravenous infusion will be administered on Day 1 of each 21 day cycle together with chemotherapy (intravenous nanoparticle albumin-bound paclitaxel, or gemcitabine–carboplatin) administered per standard of care protocol] and ARM B cohort 2 [paxalisib 30 mg (2 x 15 mg capsule) administered orally once daily in 21 day cycles; pembrolizumab 200 mg (100 mg/4 mL) intravenous infusion will be administered on Day 1 of each 21 day cycle together with chemotherapy (intravenous nanoparticle albumin-bound paclitaxel, or gemcitabine–carboplatin) administered per standard of care protocol].
Control group
Dose comparison

Outcomes
Primary outcome [1] 339420 0
Safety and Tolerability
Timepoint [1] 339420 0
ARM A:
Cycle 1: Baseline, Day 1, Day 8, Day 15
Cycle 2 and 3: Day 1, Day 15
Cycle 3 onwards: Day 1, Day 15 (phone call)
Day 29 of last cycle and 28 days post final dose

ARM B:
Cycle 1, 2 and 3: Baseline, Day 1, Day 8, Day 15
Cycle 4 onwards: Day 1, Day 8 (phone call)
Day 22 of last cycle and 28 days post final dose
Secondary outcome [1] 439893 0
Circulating tumour cells in the blood as a predictor of tumour recurrence assessed by using blood samples to examine number and phenotype of circulating tumour cell (CTC) using digital pathology platforms.
Timepoint [1] 439893 0
ARM A: Cycles 1, 2 and 3- Day 1; additional cycles - Day 1 of every second cycle; Day 28 of last Cycle; 28 days post final dose.
ARM B: Cycles 1, 2 and 3- Day 1; additional cycles - Day 1 of every second cycle; Day 22 of last Cycle; 28 days post final dose.
Secondary outcome [2] 439894 0
Immune cell signature as a predictor of immune reinvigoration using a scoring system for immune reinvigoration, exhaustion and checkpoint analysis. This will be assessed using blood samples to examine immune memory, checkpoint protein status and effector proteins and chemokine/cytokine expression profile using digital pathology platforms and flow cytometry
Timepoint [2] 439894 0
ARM A: Cycles 1, 2 and 3- Day 1; additional cycles - Day 1 of every second cycle; Day 28 of last Cycle; 28 days post final dose.
ARM B: Cycles 1, 2 and 3- Day 1; additional cycles - Day 1 of every second cycle; Day 22 of last Cycle; 28 days post final dose.
Secondary outcome [3] 439920 0
Progression free survival (PFS)
Timepoint [3] 439920 0
Measurements will occur from baseline (up to 28 days before the start of the treatment Cycle 1 day 1) and then approximately every 8 weeks during dosing for 12 months or until the criteria for disease progression is met (or death occurs) or date of last follow up.
Secondary outcome [4] 441014 0
Objective response rate (ORR)
Timepoint [4] 441014 0
Measurements will occur from baseline (up to 28 days before the start of the treatment Cycle 1 day 1) and then approximately every 8 weeks during dosing for 12 months or until the criteria for disease progression is met (or death occurs) or date of last follow up.
Secondary outcome [5] 441015 0
Clinical benefit rate (CBR)
Timepoint [5] 441015 0
Measurements will occur from baseline (up to 28 days before the start of the treatment Cycle 1 day 1) and then approximately every 8 weeks during dosing for 12 months or until the criteria for disease progression is met (or death occurs) or date of last follow up.
Secondary outcome [6] 441016 0
Duration of response (DOR)
Timepoint [6] 441016 0
Measurements will occur from baseline (up to 28 days before the start of the treatment Cycle 1 day 1) and then approximately every 8 weeks during dosing for 12 months or until the criteria for disease progression is met (or death occurs) or date of last follow up.
Secondary outcome [7] 441017 0
Time to response (TTR)
Timepoint [7] 441017 0
Measurements will occur from baseline (up to 28 days before the start of the treatment Cycle 1 day 1) and then approximately every 8 weeks during dosing for 12 months or until the criteria for disease progression is met (or death occurs) or date of last follow up.
Secondary outcome [8] 441018 0
Time to progression (TTP)
Timepoint [8] 441018 0
Measurements will occur from baseline (up to 28 days before the start of the treatment Cycle 1 day 1) and then approximately every 8 weeks during dosing for 12 months or until the criteria for disease progression is met (or death occurs) or date of last follow up.
Secondary outcome [9] 441019 0
Overall survival (OS)
Timepoint [9] 441019 0
Participant survival will be monitored continuously throughout the course of the study. Following End of Treatment, all best efforts will be made to retain subjects in long term follow up for survival. These survival assessments may be performed remotely via telephone or by examination of medical records every 6 months until the official completion or discontinuation of the study itself.
Secondary outcome [10] 441020 0
Objective intracranial response rate (iORR) of participants with brain metastases
Timepoint [10] 441020 0
Measurements will occur from baseline (up to 28 days before the start of the treatment Cycle 1 day 1) and then approximately every 8 weeks during dosing for 12 months or until the criteria for disease progression is met (or death occurs) or date of last follow up.
Secondary outcome [11] 441021 0
Intracranial clinical benefit rate (iCBR) of participants with brain metastases
Timepoint [11] 441021 0
Measurements will occur from baseline (up to 28 days before the start of the treatment Cycle 1 day 1) and then approximately every 8 weeks during dosing for 12 months or until the criteria for disease progression is met (or death occurs) or date of last follow up.

Eligibility
Key inclusion criteria
1. Participants must be female and at least 18 years of age inclusive, at the time of signing the informed consent.
2. Participants who are:
Arm A, Paxalisib plus Olaparib:
a. HER2-negative stage IV (metastatic) breast cancer diagnosis based on pre-existing documented histopathology and medical imaging results.
b. Confirmed gBRCAm (BRCA1, BRCA2 or both)
c. Prior treatment with chemotherapy in the metastatic setting.
Arm B, Paxalisib plus Pembrolizumab/chemotherapy:
a. Recurrent, unresectable or metastatic triple-negative breast cancer diagnosis, based on preexisting documented histopathology and medical imaging results.
b. Confirmed PD-L1 (CPS greater than or equal to 10) positive.
c. Treatment in combination with chemotherapy.
d. No prior PD-1/PD-L1 therapy.
3. Contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies and with the applicable Consumer Medicines Information Sheet/s for the non-investigational medicinal products.
4. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
5. Life expectancy greater than 12 weeks
6. At least one confirmed measurable lesion by RECIST 1.1 criteria (iRECIST for Arm B)
7. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
8. Satisfies the following haematologic, renal and hepatic function tests:
a. Haematologic tests:
- Absolute neutrophil count greater than or equal to 1.5 x 10^9L
- Platelets greater than or equal to 100 x 10^9L
- Haemoglobin greater than or equal to 90 g/L
b. Blood coagulation tests:
- Prothrombin time (PT) less than or equal to 1.5 x upper limit of normal (ULN)
- Activated partial thromboplastin time (aPTT) less than or equal to 1.5 x ULN
c. Hepatic function tests:
- Total bilirubin less than or equal to 1.5 x ULN
- AST and ALT less than or equal to 2.5 x ULN [less than or equal to 5 x ULN in case of liver metastases]
d. Renal function tests:
- Creatinine less than or equal to 1.5 x ULN OR creatinine clearance (CrCl) greater than or equal to 30 mL/min for a patient with creatine levels greater than 1.5 x ULN
9. Willing and able to comply with the protocol as judged by the Investigator
10. Patients must be willing to forego other drug therapy against the tumor while enrolled in the study.
Minimum age
18 Years
Maximum age
No limit
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Known hypersensitivity to any excipients of paxalisib formulation or of other PI3K/mTOR inhibitors
2. Type 1 diabetes, uncontrolled type 2 diabetes (HbA1C greater than 9.0% [75 mmol/mol]) or use of insulin therapy
3. Significant medical illnesses that in the Investigator's opinion cannot be adequately controlled or would compromise the patient's ability to tolerate this therapy
4. Women who are pregnant or who are lactating. NOTE: Serum pregnancy test to be assessed within 7 days prior to first dose
5. Any previous malignancy; except for adequately controlled limited basal cell carcinoma of the skin, DCIS, squamous carcinoma of the skin or carcinoma in situ of the cervix, or any previous malignancy which has been absent of evidence of disease and has not required treatment for greater than or equal to 2 years
6. Patients who have any other disease that would in the judgement of the investigator, exclude enrollment in this study.
a. Disease could be either metabolic or psychological, and based upon any evidence on clinical examination or special investigations (including a laboratory finding)
b. Any disease states that require treatment with immunosuppressants (e.g. rheumatoid arthritis).
7. Use of any strong CYP3A4 inducing or inhibiting agents within 14 days of first dose of paxalisib.
8. Recent history of antitumor therapy administered with the intent of treating cancer prior to study entry. Exclusion periods prior to Cycle 1 Day 1 defined as: 4 weeks for radiotherapy, 6 weeks for nitrogen mustard type alkylating agents, 4 weeks for monoclonal antibodies, 3 weeks for standard chemotherapy, and 2 weeks or 5 half-lives for small molecule targeted agents and hormonal therapy.
9. Major surgery, as defined by the Investigator within 28 days prior to Day 1
10. Any other investigational drug or participation in another investigational study within 28 days prior to Day 1
11. QTc interval time of greater than or equal to 470 msec
12. Unable to comply with the administration of the study treatment

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



Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
25/11/2024
Actual
Date of last participant enrolment
Anticipated
20/12/2025
Actual
Date of last data collection
Anticipated
20/12/2026
Actual
Sample size
Target
24
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 27133 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [2] 27134 0
Sunshine Coast University Hospital - Birtinya
Recruitment hospital [3] 27135 0
Gold Coast University Hospital - Southport

Funding & Sponsors
Funding source category [1] 317455 0
Commercial sector/Industry
Name [1] 317455 0
Kazia Therapeutics
Country [1] 317455 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Kazia Therapeutics
Address
Country
Australia
Secondary sponsor category [1] 319752 0
Commercial sector/Industry
Name [1] 319752 0
Beyond Drug Development
Address [1] 319752 0
Country [1] 319752 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 316170 0
Metro North Health Human Research Ethics Committee A
Ethics committee address [1] 316170 0
Ethics committee country [1] 316170 0
Australia
Date submitted for ethics approval [1] 316170 0
31/07/2024
Approval date [1] 316170 0
24/10/2024
Ethics approval number [1] 316170 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 137014 0
Dr Michelle Nottage
Address 137014 0
Royal Brisbane and Women's Hospital Herston, Queensland, Australia, 4006
Country 137014 0
Australia
Phone 137014 0
+61736467712
Fax 137014 0
Email 137014 0
Michelle.Nottage@health.qld.gov.au
Contact person for public queries
Name 137015 0
Michelle Nottage
Address 137015 0
Royal Brisbane and Women's Hospital Herston, Queensland, Australia, 4006
Country 137015 0
Australia
Phone 137015 0
+61736467712
Fax 137015 0
Email 137015 0
Michelle.Nottage@health.qld.gov.au
Contact person for scientific queries
Name 137016 0
Michael Fitzgerald
Address 137016 0
Kazia Therapeutics Limited, Level 34, 300 Barangaroo Avenue, Sydney New South Wales 2000
Country 137016 0
Australia
Phone 137016 0
+19198039988
Fax 137016 0
Email 137016 0
michael.fitzgerald@kaziatherapeutics.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided


Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.