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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT03900884
Registration number
NCT03900884
Ethics application status
Date submitted
1/04/2019
Date registered
3/04/2019
Date last updated
23/05/2024
Titles & IDs
Public title
Palbociclib, Letrozole & Venetoclax in ER and BCL-2 Positive Breast Cancer
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Scientific title
A Phase 1b Study of Palbociclib, Letrozole and Venetoclax in ER and BCL-2 Positive Locally Advanced or Metastatic Breast Cancer
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Secondary ID [1]
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18/028
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Universal Trial Number (UTN)
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Trial acronym
PALVEN
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Breast Neoplasm Female
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Condition category
Condition code
Cancer
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Breast
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - Venetoclax
Treatment: Drugs - Palbociclib
Treatment: Drugs - Letrozole
Experimental: Letrozole + Palbociclib + Venetoclax - The Letrozole dose is 2.5 mg (D1-28) for all dose levels.
Starting dose Level 1: Palbociclib 100 mg (D1-21) and Venetoclax 100 mg (D1-21) daily.
Treatment: Drugs: Venetoclax
At commencement of study: Venetoclax will commence at 100 mg daily (oral) for days 1-21 of each 28 day cycle. This is a dose finding study so doses will be adjusted between 100 and 800 mg/day depending on dose escalation results and recommendation of the safety committee.
Treatment: Drugs: Palbociclib
At commencement of study: Palbociclib will commence at 100 mg daily (oral) for days 1-21 of each 28 day cycle. This is a dose finding study so doses will be adjusted between 75 and 125 mg/day depending on dose escalation results and recommendation of the safety committee.
Treatment: Drugs: Letrozole
Letrozole will be dosed daily at a fixed dose of 2.5 mg/day throughout the study.
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Determination of the Maximum Tolerated Dose (MTD), dose-limiting toxicities (DLTs) and recommended phase 2 dose of drug combination of palbociclib, letrozole and venetoclax.
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Assessment method [1]
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To determine the MTD and DLTs of the combination of palbociclib, letrozole and venetoclax in ER positive, BCL-2 positive, HER2 negative metastatic breast cancer or locally advanced breast cancer not amenable to surgical or local therapy with curative intent, and to identify the recommended Phase 2 dose.
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Timepoint [1]
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36 months
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Secondary outcome [1]
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Safety profile of the combination of palbociclib, letrozole and venetoclax: CTCAE V 5
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Assessment method [1]
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Toxicities measured using CTCAE V 5
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Timepoint [1]
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maximum 36 months
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Secondary outcome [2]
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Response Rate
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Assessment method [2]
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To describe the best response (according to RECIST v1.1), defined as Complete Response (CR) or Partial Response (PR) or stable disease (SD) at 24 weeks.
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Timepoint [2]
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24 weeks
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Secondary outcome [3]
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Overall survival
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Assessment method [3]
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Overall survival (OS) defined as the time from commencement of the study to date of death from any cause
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Timepoint [3]
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36 months
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Secondary outcome [4]
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Clinical benefit rate
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Assessment method [4]
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To estimate clinical benefit rate (CBR), defined as CR, PR or SD.
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Timepoint [4]
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36 months
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Secondary outcome [5]
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Patient reported outcomes
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Assessment method [5]
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Defined as treatment-related symptoms, patient functioning, and health-related quality of life associated with venetoclax in combination with palbociclib and letrozole. Assessed through patient reported outcomes using a validated quality of life questionnaire - EORTC QLQ C30. The questionnaire is deigned to evaluate change in quality of life over time. Outcomes are rated by the patient on a numerical scale over 28 questions of between 1-4 With 1 being no issue to 4 being a significant issue. There are an additional 2 questions regarding overall quality of life which are rated on a numerical scale 1-7 with 1 being the poorest and 7 being excellent.
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Timepoint [5]
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36 months
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Eligibility
Key inclusion criteria
1. Patient has provided written informed consent for the main PALVEN study.
2. Female patients = 18 years of age at screening.
3. Postmenopausal, defined as:
1. Age =60 years, or
2. Age <60 years and undergone bilateral oophorectomy or medically confirmed ovarian
failure, or
3. Age <60 years and have cessation of regular menses for at least 12 consecutive
months with no alternative pathological or physiological cause and have serum
levels of oestradiol and FSH within the reference range for postmenopausal
females.
4. If pre or peri menopausal, patients must be willing to receive ovarian
suppression/ablation, commencing =28 days prior to first dose of treatment.
5. Eastern Cooperative Oncology Group (ECOG) performance status score = 1. (Appendix 1).
6. Patient must have histological or cytological confirmation of metastatic carcinoma of
the breast (either from the primary or metastatic site) or locally advanced breast
cancer not amenable to surgical or local therapy with curative intent, with the
following tumour molecular characteristics (as determined from pre-screening testing):
1. ER positive (defined as =10% positive stained carcinoma cells).
2. BCL-2 positive (defined as =50% cells with at least moderate cytoplasmic
staining; intensity 2-3 on a 0-3 scale).
3. HER2 non-amplified (per ASCO/CAP guidelines).
7. Patients must be willing to provide tissue after two weeks of treatment from a newly
obtained core or excisional biopsy of a tumour lesion where feasible. Patients for
whom a repeat biopsy cannot be provided (e.g. inaccessible or patient safety concern)
may be eligible only upon agreement from the Coordinating Principal Investigator.
8. Patients have received no more than a total of two prior lines of systemic therapy for
metastatic breast cancer. This can include one line of chemotherapy.
9. Patients must have measurable disease (according to RECIST v1.1) or evaluable disease.
Bone-only metastases are allowed.
10. Patents must have adequate organ and bone marrow function as defined below within 14
days prior to registration:
- Haemoglobin = 90 g/L.
- Absolute neutrophil count = 1.5 x 109/L.
- Platelet count = 100 x 109/L.
- ALT and AST = 2.5 x upper limit of normal (ULN), or = 5 x ULN if liver metastases
are present.
- Total serum bilirubin = 1.5 x ULN. Patient's with Gilbert's syndrome may have a
total serum bilirubin > 1.5 x ULN.
- Creatinine Clearance = 50 mls/min (Cockcroft-Gault, please see Appendix 2).
11. Female patients of childbearing potential must have negative urine or serum pregnancy
test within 14 days prior to registration.
12. Life expectancy > 6 months.
13. Patient is able to swallow whole tablets.
14. Female patients of childbearing potential must be willing to use at least one of the
following methods of contraception for the course of the study through to 30 days
after the last dose of study medication:
- Total abstinence from sexual intercourse as the preferred lifestyle of the
patient (periodic abstinence is not acceptable).
- Intrauterine device (IUD) or Mirena.
- Double-barrier method (contraceptive sponge, diaphragm or cervical cap with
spermicidal jellies or cream and a condom).
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Females
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Can healthy volunteers participate?
No
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Key exclusion criteria
1. Patients who have previously been exposed to venetoclax (ABT-199) or a CDK4/6
inhibitor (in the adjuvant or metastatic setting).
2. Patients who are pregnant or lactating.
3. Patients with evidence of CNS metastases.
4. Receipt of any anti-cancer therapy received within 21 days of registration including
chemotherapy, radiotherapy, endocrine therapy (aromatase inhibitors, Selective
Estrogen Receptor Modulator such as tamoxifen, or a Selective Estrogen Receptor
Degrader such as fulvestrant) or other investigational therapy. The following
therapies ARE permitted:
1. Bisphosphonate or denosumab therapy for patients with bone metastases.
2. Ovarian suppression in pre- and peri-menopausal patients.
5. Prior radiotherapy to a target lesion site, unless there has been unequivocal
progression at that site following radiotherapy.
6. Patients who are taking warfarin or other oral anticoagulant therapy. The use of
alternative anticoagulation therapy such as systemic low-molecular weight heparin will
be acceptable.
7. Patients who have had major surgery within 28 days of first dose of study drug or
anticipation of the need for major surgery during the course of study treatment.
8. Patients that have received any of the following agents within 7 days prior to
registration:
1. Steroid therapy for anti-neoplastic intent.
2. CYP3A inhibitors e.g. fluconazole, ketoconazole, clarithromycin.
3. Potent CYP3A inducers e.g. rifampicin, carbamazepine, phenytoin, St. John's Wort.
4. Drugs that are known to prolong the QT interval (see Appendix 5).
9. Consumption of one or more of the following within 3 days prior to the first dose of
study drugs:
1. Grapefruit or grapefruit products.
2. Seville oranges including marmalade containing Seville oranges.
3. Star fruit (carambola).
10. Need for current chronic corticosteroid therapy (=10 mg of prednisone per day or an
equivalent dose of other corticosteroids).
11. Patients with active uncontrolled infection.
12. Patients with a known history of human immunodeficiency virus (HIV) infection, chronic
Hepatitis B or C.
1. Patients who are positive for HCV antibody must be negative for HCV by polymerase
chain reaction (PCR) to be eligible.
2. Patients with a post or resolved hepatitis B virus (HBV) infection (defined as
having a positive HBcAb and negative HbsAg) may be included if HBV DNA is
undetectable. These patients must be willing to undergo monthly DNA testing.
13. Administration of live, attenuated vaccine within 28 days prior to registration or
anticipation of need for such a vaccine during the study.
14. Patients with a history of other malignancies within the past 5 years except for
treated skin basal cell carcinoma (BCC), squamous cell carcinoma (SCC), malignant
melanoma =1.0mm without ulceration, localised thyroid cancer, or cervical carcinoma in
situ. Other malignancies considered to be at low risk of recurrence may also be
included according to the discretion of the Investigator.
15. Patients with visceral spread at risk of short-term life-threatening complications.
16. Patients with a history of medical or psychiatric conditions that may interfere with
the patient's participation in the study.
17. Patients on contraception that is oestrogen or progestin based (Mirena accepted).
18. Patients who are on Hormone Replacement Therapy.
19. Patients with a QTc = 480 msec (based on the mean value of the triplicate ECGs),
family or personal history of long or short QT syndrome, Brugada syndrome or known
history of QTc prolongation, or Torsade de Pointes
20. Patients with an uncontrolled electrolyte disorder that can compound the effects of a
QTc-prolonging drug (e.g. hypocalcemia, hypokalemia, hypomagnesemia)
21. History of a malabsorption syndrome or other condition that would interfere with
enteral absorption of study drugs.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
N/A
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Single group
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Other design features
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Phase
Phase 1
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Active, not recruiting
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
25/09/2019
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
1/12/2025
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Actual
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Sample size
Target
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Accrual to date
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Final
17
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Recruitment in Australia
Recruitment state(s)
VIC
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Recruitment hospital [1]
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Peter MacCallum Cancer Centre - Melbourne
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Recruitment hospital [2]
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Royal Melbourne Hospital - Melbourne
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Recruitment hospital [3]
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Austin Health - Melbourne
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Recruitment postcode(s) [1]
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3000 - Melbourne
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Recruitment postcode(s) [2]
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3052 - Melbourne
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Recruitment postcode(s) [3]
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3084 - Melbourne
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Funding & Sponsors
Primary sponsor type
Other
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Name
Peter MacCallum Cancer Centre, Australia
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Address
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Country
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Ethics approval
Ethics application status
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Summary
Brief summary
This study is investigating the combination of palbociclib, letrozole and venetoclax in ER
and BCL-2 positive locally advanced or metastatic breast cancer.
It is hypothesised that venetoclax may augment the actions of palbociclib and letrozole in
these patient groups. The primary objective of the study is to determine the maximum
tolerated dose of the combination treatment, which can be used in subsequent studies. The
study will also investigate disease response and survival.
Participants will receive palbociclib (daily, on days 1-21 of each 28 day cycle), letrozole
(daily, on days 1-28 of each 28 day cycle) and venetoclax (daily, on days 1-21 of each 28 day
cycle) until the last patient has completed 18 months treatment on the study.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT03900884
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Geoffrey Lindeman, MBBS FRACP PhD
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Address
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Peter MacCallum Cancer Centre, Australia
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Country
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Phone
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Fax
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Email
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Contact person for public queries
Name
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Address
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Country
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Phone
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Fax
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Email
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT03900884
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