None listed
Conditions
Brief summary
This study will investigate the safety, tolerability (how well a substance is tolerated by patients), and pharmacokinetics (PK, the measure of how the human body processes a substance) of different doses of Auceliciclib in patients with advanced solid tumours, locally advanced or metastatic cancer or high-grade glioma. Who is it for? You may be eligible to join this study if you are aged 18 and above, have been diagnosed with locally advanced or metastatic cancer (all solid tumours), locally advanced or metastatic cancer or high-grade glioma. Study details There are two stages to this study: 1) Dose escalation stage where 7 different doses of Auceliciclib will be used to determine the maximum tolerated dose for Auceliciclib in participants with any solid tumor. Each dose is administered once or twice daily (depending on cohort) on Day 1-28 of each 28 day cycle. 2) Recurrent GBM Combination Therapy Auceliciclib + TMZ combination therapy: Auceliciclib will be administered either once daily on Day 1-21 of each 28 -Day cycle or twice daily for Day 1-28 of each 28-Day cycle. TMZ will be administered concurrently once daily for Day 1-21 or Day 1-28 of each 28-Day cycle. Safety and tolerability will be assessed frequently in every cycle for both stages. PK for Auceliciclib in each cancer type will be assessed using blood samples. It is hoped Auceliciclib will demonstrate potent and superior growth inhibition of cancer cells, improving overall survival with less associated toxicities than other similar compounds in patients with advanced solid tumors.
Interventions
This is a Phase 1/2, open-label, dose-exploration, expansion and/combination study.
The Phase 1 part of the study will assess the safety and tolerability of Auceliciclib and identify the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) for Auceliciclib alone and in combination with Temozolomide (TMZ).
The Dose Escalation Phase (Phase 1a) Auceliciclib monotherapy will involve participants with locally advanced or metastatic cancer (all solid tumours allowed). Each treatment cycle i
This is a Phase 1/2, open-label, dose-exploration, expansion and/combination study. The Phase 1 part of the study will assess the safety and tolerability of Auceliciclib and identify the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) for Auceliciclib alone and in combination with Temozolomide (TMZ). The Dose Escalation Phase (Phase 1a) Auceliciclib monotherapy will involve participants with locally advanced or metastatic cancer (all solid tumours allowed). Each treatment cycle is 28 days, with participants treated with oral Auceliciclib per the planned dose schedule below. Dose Escalation Phase (Phase 1a) Monotherapy planned doses are: • Dose level 1: 50 mg once daily on Days 1-21 of each 28-day cycle • Dose level 2: 100 mg once daily on Days 1-21 of each 28-day cycle • Dose level 3: 150 mg once daily on Days 1-21 of each 28-day cycle • Dose level 4: 250 mg once daily on Days 1-21 of each 28-day cycle • Dose level 5: 350 mg once daily on Days 1-21 of each 28-day cycle • Dose level 6a: 175mg twice daily on Days 1-28 of each 28 day cycle • Dose level 6b: 250mg twice daily on Days 1-28 of each 28 day cycle • Dose level 6c: 500mg twice daily on Days 1-28 of each 28 day cycle The Auceliciclib and TMZ Combination Therapy Phase (Phase 2a) involves participants with recurrent progressive high grade glioma (e.g GBM). As a potential treatment for GBM, this protocol is exploring two ways of administering TMZ with Auceliciclib across 28-day cycles as follows and per the planned dose schedule below: 1) administering Auceliciclib with standard of care TMZ (Cohorts 4c and 5c). 2) administering Auceliciclib with metronomic TMZ dosing (cohorts 1-6b). Combination Therapy (Phase 2a) planned doses are: • Dose level 1b: Auceliciclib 100mg once daily and TMZ 100mg once daily on Days 1-21 of each 28-day cycle • Dose level 2b: Auceliciclib 150mg once daily and TMZ 100mg once daily on Days 1-21 of each 28-day cycle • Dose level 3b: Auceliciclib 100mg twice daily on Days 1-28 and TMZ 100mg once daily on Days 1-21 of each 28-day cycle • Dose level 4b: Auceliciclib 150mg twice daily on Days 1-28 and TMZ 100mg once daily on Days 1-21 of each 28-day cycle • Dose level 5b: Auceliciclib 300mg twice daily on Days 1-28 and TMZ 100mg once daily on Days 1-28 of each 28-day cycle • Dose level 6b: Auceliciclib 500mg twice daily on Days 1-28 and TMZ 100mg once daily on Days 1-28 of each 28-day cycle An additional 1-6 participants per cohort may be enrolled for compassionate access. Additional participants are optional based on time critical disease and demand by participants requesting to be enrolled onto trial due to lack of available treatment options. Patients will continue on the study until they are no longer considered to be achieving clinical benefit (i.e. disease progression), they have unacceptable toxicity, they withdraw informed consent, or are withdrawn from the study. The study timeframe will include a 28-day screening period, 28-day treatment cycles, and a follow-up visit 4-6 weeks from the last dose of study treatment. Patients will also be requested to participate in long-term follow-up to assess overall survival. Contact will be made with the patient via telephone approximately every 3 months, commencing 90 days (±2 weeks) after the last dose of study treatment. Long-term follow-up will continue for at least 1 year after the last dose of study treatment. Auceliciclib will be administered orally in capsule form.
Sponsors
Aucentra Therapeutics Pty Ltd.
Study design
Allocation
Non-randomised trial
Intervention model
Other
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Ability to understand and be willing to sign an informed consent form. 2. Male or female, greater than or equal to 18 years old at the time of screening. 3. Diagnosis of histologically or cytologically confirmed: a. Locally advanced or metastatic cancer (all solid tumours allowed). Patients must be considered refractory or intolerant to standard-of-care (SOC) therapies or have refused SOC therapy (Phase 1a, monotherapy), OR b. Locally advanced or metastatic cancer that are thought to respond to CDK4/6 inhibition, or non-malignant tumours impacting QOL (e.g. teratoma’s, invasive neurofibroma’s) that may respond to CDK4/6 inhibition (based on optional tumour molecular/genetic profile). Patients must be considered refractory or intolerant to SOC therapies or have refused SOC therapy, or have invasive non malignant tumours that cannot be treated with surgery alone (Phase 1b, monotherapy), OR c. High-grade glioma, such as GBM. Patient must also: i. Have completed radiation therapy, with concomitant TMZ plus a minimum of 1-3 full cycles of TMZ monotherapy post RTx/CTx as their SOC first-line treatment. ii. Have recurrent/progressive high-grade glioma >/= 3-6 months post first-line SOC treatment. 4. ECOG performance status of 0 to 2. 5. Able to take oral medications. 6. QT interval corrected using the Fridericia method (QTcF) less than or equal to 450 msec for males and less than or equal to 460 msec for females at screening and on Day 1, prior to dose administration. 7. Evidence of adequate cardiac function. 8. Evidence of adequate hepatic function at screening. 9. Adequate haematology laboratory assessment at screening. 10. Adequate renal function. 11. Adequate coagulation laboratory assessments at screening. 12. Female patients must a. Be of non-child-bearing potential, or b. If of child-bearing potential, must agree not to attempt to become pregnant. 13. Male patients must agree not to donate sperm and if engaging in sexual intercourse with a female partner who could become pregnant, must agree to use an acceptable method of contraception 14. Estimated life expectancy of at least 3 months, in the opinion of the Investigator. 15. Willing and able to comply with all scheduled visits, treatment plans, laboratory tests, and other study procedures.
Exclusion criteria
1. Prior treatment with a CDK4/6 inhibitor, unless first approved by medical monitor. 2. Patients with symptomatic primary central nervous system (CNS) tumour, symptomatic CNS metastases, or untreated spinal cord compression that have moderate or severe symptoms. 3. Uncontrolled pleural effusion(s), pericardial effusion or ascites. 4. Evidence of abnormal cardiac function. 5. Cardiac arrhythmia that is considered unstable and requiring medication for stabilisation. 6. Unable to swallow oral medications. 7. Gastrointestinal (GI) conditions that, in the opinion of the Investigator, could affect the absorption of study drug. 8. History of other malignancy within the past 2 years.
Outcome results
None listed