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Trial registered on ANZCTR


Registration number
ACTRN12621001419853
Ethics application status
Approved
Date submitted
25/06/2021
Date registered
21/10/2021
Date last updated
30/06/2022
Date data sharing statement initially provided
21/10/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
A Study of OP-1250 in Combination with the CDK4/6 Inhibitor Palbociclib in Adult Subjects with Advanced or Metastatic hormone receptor-positive (HR-positive), human epidermal growth factor receptor 2-negative (HER2-negative) Breast Cancer
Scientific title
A Phase 1 Dose Escalation and Dose Expansion Open-label, Multicenter, Study of OP-1250 in Combination with the CDK4/6 Inhibitor Palbociclib in Adult Subjects with Advanced or Metastatic HR-positive, HER2-negative Breast Cancer
Secondary ID [1] 304319 0
OP-1250-002
Universal Trial Number (UTN)
Trial acronym
Linked study record
NCT05266105

Health condition
Health condition(s) or problem(s) studied:
Breast Cancer 322068 0
Condition category
Condition code
Cancer 319787 319787 0 0
Breast

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
OP-1250 is a small molecule being developed as a Complete Estrogen Receptor Antagonist (CERAN) for the treatment of patients with advanced or metastatic hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) BC.
Palbociclib is a commercially available kinase inhibitor indicated for the treatment of adult subjects with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) BC advanced or metastatic breast cancer in combination either with an aromatase inhibitor as initial endocrine-based therapy or fulvestrant in patients who have received prior therapy.

The study consists of two parts:
Part 1 (Dose Escalation Phase) planned dose:
• Dose level 1: 30 mg
• Dose level 2: 60 mg
• Dose level 3: 90 mg
• Dose level 4: 120 mg
•Dose level 5: 150 mg
•Dose level 6: 210 mg
OP-1250 is dosed orally once daily in continuous 28-day cycles.
All subjects will receive OP-1250 doses in combination with oral palbociclib 125 mg once daily for 21 days in continuous 28-day cycles
In the absence of unacceptable treatment-related toxicity or disease progression, subjects may receive study treatment for up to 1 year and beyond 1 year with the agreement of the Investigator and the Sponsor. Subjects who discontinue OP-1250 must also discontinue palbociclib within the context of this protocol.
Each cohort will be administered to a distinct group of subjects. Subjects in each cohort will continue to receive treatment as per above, at the assigned dose level, or at a reduced dose if required based on any toxicities that occur after the end of the DLT period.
Intra-subject dose escalation is not permitted during dose escalation. However, once a RP2D is determined, subjects enrolled on the Phase I part of the study may be treated at the RP2D with approval of the Medical Monitor, if the PI or designee considers this in the best interest of the subject after discussion with the Medical Monitor.
The DLT period is one cycle (Cycle 1). 3 patients are required per cohort (unless the cohort is required to be expanded to replace a subject who is not evaluable for dose escalation, or for a DLT). The last of the subjects in the cohort is to have completed the DLT period before the safety review is performed, and decision made to escalate to the next cohort. The actual number of days is dependent upon a number of factors including extraction of listings from the database for safety review, availability of members for safety review meeting etc. One week between cohorts is a reasonable assumption.
Subjects are provided with a Dosing Diary to record daily administration of their study treatment. This would include any missed doses. This is reviewed by the study team at each clinic visit and any deviations from dosing schedule discussed with the subject. Also, empty bottles and any unused capsules/tablets are returned at every clinic visit for a pill count to be performed by the study team to check compliance. This will be reconciled against the subject dosing diary.

Part 2 (Dose Expansion): This portion of the study further explores the safety and Pharmacokinetics of OP-1250 in combination with Palbociclib and to determine the recommended Phase II dose (RP2D) of OP-1250.
The MTD is defined as the highest feasible dose tested in which greater than 33% (ie, less than or equal to 1 of 6) subjects experienced a DLT attributable to the study drug, when at least 6 subjects were treated at that dose and were assessable for toxicity. The RP2D will be determined after review of all the available safety and PK data. Additionally, there is an ongoing dose escalation/expansion study of OP-1250 monotherapy that may also be used to inform the decision re RP2D that will be used in Part 2.
OP-1250 is dosed orally once daily in continuous 28-day cycles.
As for Part 1; ongoing in the absence of unacceptable treatment-related toxicity or disease progression/whilst the patient is deriving clinical benefit per investigator discretion, for up to 12 months or longer if agreed by the investigator and sponsor.
Part 2 will commence when the RP2D (dose to be taken into Part 2) has been determined. This will occur after the end of the DLT period for the last dose escalation cohort to be evaluated. The exact time between study parts will depend upon availability of all safety and PK data needed to make the dose determination. Delays are not anticipated
Participant groups between study parts are distinct.





Intervention code [1] 320664 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 327648 0
Part 1: To assess the incidence of dose limiting toxicities (DLT) during the first cycle of treatment with OP-1250 in combination with palbociclib.
Dose limiting toxicity is defined as the occurrence of any of the protocol specified 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) during C1, except those that are clearly due to disease progression (PD) or extraneous causes.
Timepoint [1] 327648 0
Part 1: The dose-limiting toxicity (DLT) period is Cycle 1 of treatment in Part 1 subjects who receive at least 75% of planned doses assessed daily from Day 1 to Day 28 post-first dose
Primary outcome [2] 327649 0
Part 1/Part 2: To assess the safety and tolerability of OP-1250 when administered in combination with palbociclib assessed by
1. incidence of adverse events and serious adverse events according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (NCI CTCAE, v5.0),
2. physical examinations,
3. 12-lead ECGs, clinical laboratory assessments (Hematology, Clinical Chemistry and urinalysis),
4. vital signs (systolic and diastolic blood pressure, pulse, respiration rate, temperature, weight).
Timepoint [2] 327649 0
Part 1/ Part 2: From first dose of study treatment to 30 days post last dose of study treatment
Primary outcome [3] 327650 0
Part 1/Part 2: To assess the pharmacokinetics (PK) of OP-1250 and palbociclib when administered in combination.
Pharmacokinetics parameter includes: maximum concentration (Cmax), minimum concentration (Cmin), time to maximum concentration (Tmax), area under the curve (AUC), terminal elimination half-life (t1/2) and concentrations at steady state
Timepoint [3] 327650 0
Plasma PK samples for OP-1250 will be obtained for all subjects according to the schedule defined in the protocol starting at Cycle 1 Day 1 until Cycle 9 Day 1 for OP-1250 and Cycle 3 Day 15 for palbociclib. Sampling timepoints are C1D1: pre-dose, 0.5 hour (±15 mins), 1 hour (±15 mins), 2 hours (± 30 mins), 4 hours (± 30 mins), 6 hours (± 30 mins) post-dose, and C1D2 pre-dose (ie, 24 ±2 hours post C1D1 dose). Plasma PK samples for OP-1250 will also be obtained on C1D8/C1D15: pre-dose, C2D15: pre-dose, 0.5 hour (±15 mins), 1 hour (±15 mins), 2 hours (±30 mins), 4 hours (±30 mins), and 6 hours (±30 mins) post-dose, C2D16: pre-dose (ie, 24 ±2 hours post C2D15 dose), C3D1: pre-dose, C3D15: pre-dose, and for C5, C7 and C9 pre-dose on D1.
Plasma PK samples for palbociclib will be obtained on C1D15 pre-dose, 0.5 hour (±15 mins), 1 hour (±15 mins), 2 hours (±30 mins), 4 hours (±30 mins), and 6 hours (±30 mins). Plasma PK samples for palbociclib will also be obtained on C2D15: pre-dose and C3D15: pre-dose.
An unscheduled PK blood sample should be drawn before a daily OP-1250 dose (trough sample) as soon as possible after an SAE, and pre-dose at a clinic visit at least 1 week following a dose reduction of OP-1250.
Secondary outcome [1] 396563 0
Part 1/Part 2: To assess the objective response rate (ORR) of OP-1250 in combination with Palbociclib. This will be determined by investigator using Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1)
Timepoint [1] 396563 0
Part 1/Part 2: From baseline until study termination (30 days post last dose of study treatment) (as determined by radiographic and physical assessments at the frequency defined in the Schedule of Events) for each subject. Radiological (and physical) assessments/measurement of malignancy will be performed every 2 months at odd cycles starting at C3 -5d (ie, prior to commencement of next treatment cycle). For subjects who have been determined to have obtained a clinical benefit from OP-1250 the frequency of assessments will be reduced to every 3 months after the C9 assessment.
Radiographic assessments include computed tomography (CT) and magnetic resonance imaging (MRI).

Secondary outcome [2] 396564 0
Part 1/Part 2: To explore the effect of OP-1250 and Palbociclib on the QTc interval from electrocardiogram (ECGs)
Timepoint [2] 396564 0
Part 1/ Part 2: ECGs will be obtained for all subjects according to the schedule defined in the protocol starting at screening (baseline) until Cycle 9 Day 1. Assessment timepoints are Screening, C1D1: pre-dose and 4 hours (± 30 mins) post-dose, C1D8/C1D15: pre-dose, C2D15: pre-dose and 4 hours (±30 mins) post-dose, C3D1: pre-dose, C3D15: pre-dose, and for C5, C7 and C9 pre-dose on D1. An unscheduled ECG should be performed before a daily OP-1250 dose (trough sample) as soon as possible after an SAE, and pre-dose at a clinic visit at least 1 week following a dose reduction of OP-1250.
Secondary outcome [3] 398323 0
Part 1: To identify the maximum tolerated dose (MTD) of OP-1250 when administered in combination with palbociclib will be assessed by incidence of dose limiting toxicities (DLT) during the first cycle of treatment with OP-1250 in combination with palbociclib.
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)

Timepoint [3] 398323 0
Part 1: The dose-limiting toxicity (DLT) period is Cycle 1 of treatment in Part 1 subjects who receive at least 75% of planned doses assessed daily from Day 1 to Day 28 post-first dose
Secondary outcome [4] 398324 0
Part 1: To identify the recommended Phase II dose (RP2D) of OP-1250 when administered in combination with palbociclib will be assessed by incidence of dose limiting toxicities (DLT) during the first cycle of treatment with OP-1250 in combination with palbociclib.
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)

Timepoint [4] 398324 0
Part 1: The dose-limiting toxicity (DLT) period is Cycle 1 of treatment in Part 1 subjects who receive at least 75% of planned doses assessed daily from Day 1 to Day 28 post-first dose
Secondary outcome [5] 398325 0
Part 1/Part 2: To preliminarily assess the anti-tumour activity based on clinical benefit rate (CBR) of OP-1250 in combination with Palbociclib. Assessments will be done by investigator using Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1)
Timepoint [5] 398325 0
Part 1/ Part 2: From baseline until disease progression (as determined by radiographic and physical assessments at the frequency defined in the Schedule of Events) for each subject, unless death, loss to follow-up, withdrawal of consent or initiation of another anti-cancer therapy occurs first.
Radiographic and physical assessments of will be conducted at Screening/Baseline (within 28 days prior to the first study drug administration) and after every 8 weeks for the first 32 weeks. Radiographic assessments include computed tomography (CT) and magnetic resonance imaging (MRI)

Secondary outcome [6] 398326 0
Part 1/Part 2: To preliminarily assess the anti-tumour activity based duration of response (DOR) of OP-1250 in combination with Palbociclib. Assessments will be done by investigator using Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1)
Timepoint [6] 398326 0
Part 1/Part 2: From baseline until disease progression (as determined by radiographic and physical assessments at the frequency defined in the Schedule of Events) for each subject, unless death, loss to follow-up, withdrawal of consent or initiation of another anti-cancer therapy occurs first.
Radiographic and physical assessments of will be conducted at Screening/Baseline (within 28 days prior to the first study drug administration) and after every 8 weeks for the first 32 weeks. Radiographic assessments include computed tomography (CT) and magnetic resonance imaging (MRI)

Eligibility
Key inclusion criteria
1. Hormone receptor-positive (HR+)/ human epidermal growth factor receptor 2-negative (HER2-) disease, as determined in the most recently obtained archival tumor tissue sample from a metastatic site, using locally accepted criteria by the local pathology report.
2. Willing and able to participate and comply with all study requirements and to provide signed and dated informed consent prior to initiation of any study procedures.
3. Histologically- or cytologically-confirmed locally advanced or MBC for which standard curative measures do not exist.
4. Life expectancy more than 6 months, as judged by the Investigator.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Prior or concurrent malignancy whose natural history or treatment may interfere with the safety or efficacy assessment of the investigational regimen as determined by the medical monitor.
2. Known impaired cardiac function or clinically significant cardiac disease, such as ventricular arrhythmia requiring therapy, congestive heart failure (New York Heart Association Functional Classification Class 2B-4), and uncontrolled hypertension (defined as systolic blood pressure greater than 150 mm Hg and/or diastolic blood pressure greater than 100 mm Hg while on anti-hypertensive medications).
3. Myocardial infarction or unstable angina within 6 months prior to the first administration of study drug.
4. History of cerebral vascular disease within 6 months prior to the first administration of study drug.

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
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 19802 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [2] 20457 0
Breast Cancer Research Centre - Western Australia - Perth
Recruitment hospital [3] 20458 0
Barwon Health - Geelong Hospital campus - Geelong
Recruitment hospital [4] 20459 0
Icon Cancer Care South Brisbane - South Brisbane
Recruitment postcode(s) [1] 34451 0
3168 - Clayton
Recruitment postcode(s) [2] 35227 0
3220 - Geelong
Recruitment postcode(s) [3] 35228 0
4101 - South Brisbane
Recruitment postcode(s) [4] 35226 0
6000 - Perth

Funding & Sponsors
Funding source category [1] 308692 0
Commercial sector/Industry
Name [1] 308692 0
Olema Pharmaceuticals, Inc.
Country [1] 308692 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Olema Pharmaceuticals, Inc.
Address
665 3rd street, Suite #250, San Francisco, CA 94107
Country
United States of America
Secondary sponsor category [1] 309575 0
Commercial sector/Industry
Name [1] 309575 0
Olema Oncology Australia Pty Ltd
Address [1] 309575 0
C/o RSM Australia Pty Ltd, Level 13 60 Castlereagh St, Sydney NSW 2000
Country [1] 309575 0
Australia
Other collaborator category [1] 281847 0
Commercial sector/Industry
Name [1] 281847 0
Novotech (Australia) Pty Limited
Address [1] 281847 0
Level 3, 235 Pyrmont Street, Pyrmont NSW 2009
Country [1] 281847 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309365 0
Monash Health HREC
Ethics committee address [1] 309365 0
Research Support Services
Level 2, i Block,
Monash Medical Centre
246 Clayton Road
CLAYTON VIC 3168 Australia
Ethics committee country [1] 309365 0
Australia
Date submitted for ethics approval [1] 309365 0
07/09/2021
Approval date [1] 309365 0
04/10/2021
Ethics approval number [1] 309365 0
Ethics committee name [2] 309367 0
Bellberry Limited HREC
Ethics committee address [2] 309367 0
129 Glen Osmond Rd, Eastwood SA 5063
Ethics committee country [2] 309367 0
Australia
Date submitted for ethics approval [2] 309367 0
07/09/2021
Approval date [2] 309367 0
Ethics approval number [2] 309367 0

Summary
Brief summary
This study will investigate the safety, tolerability, and pharmacokinetics (a measure of how the human body processes a substance) of different doses of OP-1250, a new drug that acts to block oestrogen hormone receptors, in combination with palbociclib (an established anti-cancer drug) in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer.

Who is it for?
You may be eligible for this study if you are aged 18 or older, you have been diagnosed
with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer, and you don't have any known heart conditions including heart disease or irregular heartbeat (arrhythmia).

Study details
There are two stages to this study:
Part 1) Dose exploration stage where up to 6 different oral doses of OP-1250 will be used to determine the maximum tolerated dose for OP-1250 in participants with breast cancer. Each dose is administered daily between Days 1-28 of each 28 day treatment cycle. Participants will also be asked to take an oral dose of palbociclib for Days 1-21 of the same 28 day treatment cycle. If participants don't experience any severe side effects, they will continue to receive study treatment in 28 day cycles. A new group of participants will receive treatment at a higher dose if deemed appropriate following a review of safety from the first cycle of treatment in the prior group of participants.

Part 2) Dose Expansion stage where the recommended dose determined from the first stage will be administered to a new group of participants. Participants in this group will also receive OP-1250 daily between Days 1-28 of each 28 day cycle, and will also take an oral dose of palbociclib for Days 1-21 of the same 28 day treatment cycle. Treatment with both OP-1250 and palbociclib will continue for up to one year (or longer if agreed by the investigator and sponsor) after the first dose is administered, unless severe side effects are experienced.

Safety and tolerability will be assessed frequently in every cycle for both stages. Pharmacokinetics for OP-1250 and palbociclib will be assessed for all participants (both Part1 and Part 2) using blood samples. Participants will also be asked to complete an electrocardiogram (heart scan) every at least every second cycle for 9 months after starting in the study.

It is hoped this study will determine the safest dose of OP-1250 that can be administered to patients with breast cancer, and that this research will also show that giving OP-1250 in combination with palbociclib is safe and effective against the cancer spread.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 111330 0
Dr Daphne Day
Address 111330 0
Monash Health - Level 3 E Block, 246 Clayton Road, Clayton, VIC 3168
Country 111330 0
Australia
Phone 111330 0
+61 03 8572 2392
Fax 111330 0
Email 111330 0
daphne.day@monashhealth.org
Contact person for public queries
Name 111331 0
Dr Daphne Day
Address 111331 0
Monash Health - Level 3 E Block, 246 Clayton Road, Clayton, VIC 3168
Country 111331 0
Australia
Phone 111331 0
+61 03 8572 2392
Fax 111331 0
Email 111331 0
daphne.day@monashhealth.org
Contact person for scientific queries
Name 111332 0
Dr Jo Anne Zujewski
Address 111332 0
Olema Pharmaceuticals, Inc., 665 3rd Street, Suite #250, San Francisco, CA 94107
Country 111332 0
United States of America
Phone 111332 0
+3015258908
Fax 111332 0
Email 111332 0
jzujewski@olema.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.