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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT03900884




Registration number
NCT03900884
Ethics application status
Date submitted
1/04/2019
Date registered
3/04/2019

Titles & IDs
Public title
Palbociclib, Letrozole & Venetoclax in ER and BCL-2 Positive Breast Cancer
Scientific title
A Phase 1b Study of Palbociclib, Letrozole and Venetoclax in ER and BCL-2 Positive Locally Advanced or Metastatic Breast Cancer
Secondary ID [1] 0 0
18/028
Universal Trial Number (UTN)
Trial acronym
PALVEN
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Breast Neoplasm Female 0 0
Condition category
Condition code
Cancer 0 0 0 0
Breast

Intervention/exposure
Study type
Interventional
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.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Determination of the Maximum Tolerated Dose (MTD), dose-limiting toxicities (DLTs) and recommended phase 2 dose of drug combination of palbociclib, letrozole and venetoclax.
Timepoint [1] 0 0
36 months
Secondary outcome [1] 0 0
Safety profile of the combination of palbociclib, letrozole and venetoclax: CTCAE V 5
Timepoint [1] 0 0
maximum 36 months
Secondary outcome [2] 0 0
Response Rate
Timepoint [2] 0 0
24 weeks
Secondary outcome [3] 0 0
Overall survival
Timepoint [3] 0 0
36 months
Secondary outcome [4] 0 0
Clinical benefit rate
Timepoint [4] 0 0
36 months
Secondary outcome [5] 0 0
Patient reported outcomes
Timepoint [5] 0 0
36 months

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).
Minimum age
18 Years
Maximum age
No limit
Sex
Females
Can healthy volunteers participate?
No
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.

Study design
Purpose of the study
Treatment
Allocation to intervention
NA
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
Single group
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
25/09/2019
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
1/12/2025
Actual
Sample size
Target
Accrual to date
Final
17
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 0 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [2] 0 0
Royal Melbourne Hospital - Melbourne
Recruitment hospital [3] 0 0
Austin Health - Melbourne
Recruitment postcode(s) [1] 0 0
3000 - Melbourne
Recruitment postcode(s) [2] 0 0
3052 - Melbourne
Recruitment postcode(s) [3] 0 0
3084 - Melbourne

Funding & Sponsors
Primary sponsor type
Other
Name
Peter MacCallum Cancer Centre, Australia
Address
Country

Ethics approval
Ethics application status

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

Contacts
Principal investigator
Name 0 0
Geoffrey Lindeman, MBBS FRACP PhD
Address 0 0
Peter MacCallum Cancer Centre, Australia
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

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

No documents have been uploaded by study researchers.


Results not provided in https://clinicaltrials.gov/study/NCT03900884