None listed
Conditions
Brief summary
This study aims to learn about the safety and tolerability of the study drug, paxalisib when taken by female participants with advanced breast cancer. Who is it for? You may be eligible for this study if you are a female at least 18 years of age, with a life expectancy greater than 12 months, at least one confirmed lesion, and satisfy haematologic, renal and hepatic function tests. For Arm 1 cohort, you will need to have a HER2-negative stage IV breast cancer diagnosis, confirmed gBRCAm (BRCA1, BRCA2 or both) and prior treatment with chemotherapy in the metastatic setting. For Arm 2 cohort, you will need to have a recurrent, unresectable or metastatic triple-negative breast cancer diagnosis, confirmed PD-L1 positive, treatment in combination with chemotherapy, and no prior PD-1/PD-L1 therapy. Study details Participants in Arm A will be randomly allocated to cohort A1 or cohort A2, and administer Paxalisib (15mg or 30 mg orally once daily) plus Olaparib (300mg orally twice daily) in 28 day cycles. Participants in Arm B will be randomly allocated to cohort B1 and cohort B2, and administer Paxalisib (15 mg or 30 mg orally once daily) and Pembrolizumab (200mg intravenous infusion once daily) over 21 days together with chemotherapy (intravenous nanoparticle albumin-bound paclitaxel, or gemcitabine–carboplatin) administered per standard of care protocol. During the study period, participants will be assessed for adverse events, circulating tumour cells count, immune cell signature, and clinical activity of Paxalisib. It is hoped this research will determine whether paxalisib, when given in combination with either olaparib or pembrolizumab/chemotherapy, is safe and well tolerated, has any side effects and if there is any clinical activity that may improve outcomes for participants with advanced breast cancer.
Interventions
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 weat
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.
Sponsors
Kazia Therapeutics
Study design
Allocation
Randomised controlled trial
Intervention model
Parallel
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
No
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 neoadjuvant, adjuvant or 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 for the treatment of breast cancer in the metastatic setting. 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.
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. Monoclonal therapies for supportive care can continue. 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
Outcome results
None listed