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

NCT03900884 | Active Not Recruiting Phase 1 DMC

• 1 other identifier: 18/028
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 3

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.

Conditions

Breast Neoplasm Female

Outcome Measures

Primary Outcomes (1)

• Determination of the Maximum Tolerated Dose (MTD), dose-limiting toxicities (DLTs) and recommended phase 2 dose of drug combination of palbociclib, letrozole and venetoclax.

  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.

  36 months

Secondary Outcomes (5)

• Safety profile of the combination of palbociclib, letrozole and venetoclax: CTCAE V 5

  maximum 36 months

• Response Rate

  24 weeks

• Overall survival

  36 months

• Clinical benefit rate

  36 months

• Patient reported outcomes

  36 months

Study Arms (1)

Letrozole + Palbociclib + Venetoclax

EXPERIMENTAL

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.

Drug: Venetoclax; Drug: Palbociclib; Drug: Letrozole

Interventions

Venetoclax DRUG

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.

Letrozole + Palbociclib + Venetoclax

Palbociclib DRUG

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.

Letrozole + Palbociclib + Venetoclax

Letrozole DRUG

Letrozole will be dosed daily at a fixed dose of 2.5 mg/day throughout the study.

Letrozole + Palbociclib + Venetoclax

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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 registration:
• 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:

Sponsors & Collaborators

• Peter MacCallum Cancer Centre, Australia: lead

Study Sites (3)

Peter MacCallum Cancer Centre

Melbourne, Victoria, 3000, Australia

Location

Royal Melbourne Hospital

Melbourne, Victoria, 3052, Australia

Location

Austin Health

Melbourne, Victoria, 3084, Australia

Location

Related Publications (2)

• Rodriguez Y, Unno K, Truica MI, Chalmers ZR, Yoo YA, Vatapalli R, Sagar V, Yu J, Lysy B, Hussain M, Han H, Abdulkadir SA. A Genome-Wide CRISPR Activation Screen Identifies PRRX2 as a Regulator of Enzalutamide Resistance in Prostate Cancer. Cancer Res. 2022 Jun 6;82(11):2110-2123. doi: 10.1158/0008-5472.CAN-21-3565.

  PMID: 35405009 DERIVED

• Muttiah C, Whittle JR, Oakman C, Lindeman GJ. PALVEN: phase Ib trial of palbociclib, letrozole and venetoclax in estrogen receptor- and BCL2-positive advanced breast cancer. Future Oncol. 2022 May;18(15):1805-1816. doi: 10.2217/fon-2021-1450. Epub 2022 Feb 21.

  PMID: 35187951 DERIVED

MeSH Terms

Interventions

venetoclax; palbociclib; Letrozole

Intervention Hierarchy (Ancestors)

Nitriles; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Geoffrey Lindeman, MBBS FRACP PhD

  Peter MacCallum Cancer Centre, Australia

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This is a Phase 1b, open-label, multicentre dose escalation study of venetoclax in combination with palbociclib and letrozole in patients with ER positive and BCL-2 positive metastatic breast cancer. The study will enrol up to 36 patients with metastatic breast cancer, with the objective of defining the MTD of venetoclax in combination with palbociclib and letrozole. There will be up to a total of 6 dose levels. Three 'step-down' levels will also be included to incorporate the options of reducing the dose of palbociclib if required. The MTD will be the RP2D of palbociclib, letrozole and venetoclax.

Study Record Dates

• First Submitted: April 1, 2019
• First Posted: April 3, 2019
• Study Start: September 25, 2019
• Primary Completion: June 1, 2025
• Study Completion: December 1, 2025
• Last Updated: November 7, 2024

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will not share

Locations

AU (3)