Palbociclib Letrozole & Venetoclax in ER and BCL-2 Positive Breast Cancer

  • End date
    Mar 24, 2023
  • participants needed
  • sponsor
    Peter MacCallum Cancer Centre, Australia
Updated on 24 January 2021
platelet count
measurable disease
breast cancer
gilbert's syndrome
neutrophil count
local therapy
metastatic carcinoma


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.

Condition Breast Neoplasm Female
Treatment Letrozole, Palbociclib, venetoclax
Clinical Study IdentifierNCT03900884
SponsorPeter MacCallum Cancer Centre, Australia
Last Modified on24 January 2021


Yes No Not Sure

Inclusion Criteria

Patient has provided written informed consent for the main PALVEN study
Female patients 18 years of age at screening
Postmenopausal, defined as
Age 60 years, or
Age <60 years and undergone bilateral oophorectomy or medically confirmed ovarian failure, or
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
If pre or peri menopausal, patients must be willing to receive ovarian suppression/ablation, commencing 28 days prior to first dose of treatment
Eastern Cooperative Oncology Group (ECOG) performance status score 1. (Appendix 1)
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)
ER positive (defined as 10% positive stained carcinoma cells)
BCL-2 positive (defined as 50% cells with at least moderate cytoplasmic staining; intensity 2-3 on a 0-3 scale)
HER2 non-amplified (per ASCO/CAP guidelines)
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
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
Patients must have measurable disease (according to RECIST v1.1) or evaluable disease. Bone-only metastases are allowed
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)
Female patients of childbearing potential must have negative urine or serum pregnancy test within 14 days prior to registration
Life expectancy > 6 months
Patient is able to swallow whole tablets
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)

Exclusion Criteria

Patients who have previously been exposed to venetoclax (ABT-199) or a CDK4/6 inhibitor (in the adjuvant or metastatic setting)
Patients who are pregnant or lactating
Patients with evidence of CNS metastases
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
Bisphosphonate or denosumab therapy for patients with bone metastases
Ovarian suppression in pre- and peri-menopausal patients
Prior radiotherapy to a target lesion site, unless there has been unequivocal progression at that site following radiotherapy
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
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
Patients that have received any of the following agents within 7 days prior to
Steroid therapy for anti-neoplastic intent
CYP3A inhibitors e.g. fluconazole, ketoconazole, clarithromycin
Potent CYP3A inducers e.g. rifampicin, carbamazepine, phenytoin, St. John's Wort
Drugs that are known to prolong the QT interval (see Appendix 5)
Consumption of one or more of the following within 3 days prior to the first dose of study drugs
Grapefruit or grapefruit products
Seville oranges including marmalade containing Seville oranges
Star fruit (carambola)
Need for current chronic corticosteroid therapy (10 mg of prednisone per day or an equivalent dose of other corticosteroids)
Patients with active uncontrolled infection
Patients with a known history of human immunodeficiency virus (HIV) infection, chronic Hepatitis B or C
Patients who are positive for HCV antibody must be negative for HCV by polymerase chain reaction (PCR) to be eligible
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
Administration of live, attenuated vaccine within 28 days prior to registration or anticipation of need for such a vaccine during the study
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
Patients with visceral spread at risk of short-term life-threatening complications
Patients with a history of medical or psychiatric conditions that may interfere with the patient's participation in the study
Patients on contraception that is oestrogen or progestin based (Mirena accepted)
Patients who are on Hormone Replacement Therapy
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
Patients with an uncontrolled electrolyte disorder that can compound the effects of a QTc-prolonging drug (e.g. hypocalcemia, hypokalemia, hypomagnesemia)
History of a malabsorption syndrome or other condition that would interfere with enteral absorption of study drugs
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