Cyclin dEpendent Kinase in tRiple nEGatIVe brEast canceR - a "Window of Opportunity" Study

Phase 2

Not yet recruiting

• Conditions: Triple Negative Breast Neoplasms
• Interventions: Drug: Palbociclib; Drug: Paclitaxel; Drug: Carboplatin

• Registration Number: NCT05067530
• Lead Sponsor: Medical University of Gdansk

Brief Summary

CAREGIVER is a prospective, randomized, multicenter, open, five-arm study with unequal allocation ratios of 1:1:2:1:2 (palbociclib : paclitaxel : palbociclib + paclitaxel : carboplatin : carboplatin + paclitaxel). Study will be performed in untreated patients with triple-negative breast cancer (TNBC). Potential candidates without previously established diagnosis of TNBC will be included in a Pre-screening Phase, when a biopsy of breast tumor will be taken to confirm the diagnosis of cancer, select patients with TNBC and collect tissue for translational research.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2021-09-23
• Status Verified: 2021-10
• Study First Submitted QC: 2021-10-04
• Last Update Submitted: 2021-10-04
• Study First Posted: 2021-10-05
• Last Update Posted: 2021-10-05
• Study Start: 2022-01-01
• Primary Completion: 2025-01-01
• Study Completion: 2026-12-06

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 126

Inclusion Criteria

• females or males >18 years old at the time of informed consent signature;

• diagnosis of potentially resectable or de novo metastatic (stage II-IV) invasive carcinoma of the breast;

• eligible for standard neoadjuvant or palliative paclitaxel and/or carboplatin-based chemotherapy as determined by Investigator;

• triple negative tumor defined as:

  • hormone receptor-negative (<1% ER/PgR expression);
  • HER2-negative (Immunohistochemistry (IHC) score ≤1 or IHC score =2 and negative for the amplification by in situ hybridization);

• multicentric/multifocal disease is allowed, provided that all lesions have been biopsied and their phenotype has been confirmed pathologically as TNBC;

• no previous anticancer therapy for this malignancy;

• clinically or radiographically measurable disease (discrete lesion only, enhancement is not included) within the breast, that can be biopsied, defined as longest diameter >2 cm;

• multicentric or multifocal disease is allowed if at least 1 lesion is >2 cm;

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1;

• adequate bone marrow and organ function as defined by the following local laboratory values:

• hemoglobin ≥9 g/dL;

• absolute neutrophil count (ANC) ≥1500/μL;

• platelets ≥100,000/μL;

• total bilirubin ≤ institutional upper limit of normal (ULN), unless diagnosis of Gilbert syndrome;

• aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5x ULN;

• creatinine ≤ ULN OR creatinine clearance ≥50 mL/min per Cockcroft-Gault equation for patients with creatinine levels greater than ULN.

• blood glucose level <120 mg/dL after at least 6 hours of fasting;

• standard 12-lead electrocardiogram (ECG) without clinically significant abnormalities;

• ability to undergo contrast-enhanced MRI;

• ability to swallow and retain oral medication;

• all study participants of child-bearing potential must agree to use adequate contraceptive methods prior to study entry, during the study and for the following 3 weeks (females) or 14 weeks (males);

• prior chemotherapy, other targeted anticancer therapies, or prior radiation therapy (outside of treated breast) for other malignancy treated with radical intent is allowed, provided the treatment was completed ≥1 year before informed consent signature;

• prior bisphosphonate therapy is allowed;

• willing and able to undergo all the procedures required by the study protocol;

• provision of written informed consent form prior to receiving any study related procedure.

Exclusion Criteria

• inflammatory breast cancer;
• prior systemic treatment for this malignancy;
• prior treatment with CDK4/6 inhibitor;
• known hypersensitivity to study medications or any of their excipients;
• major surgery or radiotherapy (apart from limited field radiotherapy for symptom control) within 14 days prior to randomization;
• concurrent invasive malignancy;
• known HIV, active HBV or HCV infection;
• active autoimmune disease requiring ongoing immunosuppressive therapy;
• history of allotransplantation;
• concurrent treatment with systemic immunosuppressive agents, including steroids, within 3 weeks of enrolment;
• presence of implants or devices not compatible with MRI;
• pregnant or nursing female participants;
• receiving strong inhibitors or inducers of CYP3A4/5 or medications with narrow therapeutic window that are predominantly metabolized through CYP3A4/5;
• impairment of GI function that may significantly alter the absorption of the oral trial treatments;
• unwilling or unable to follow protocol requirements, including obligatory biopsies;
• any condition which in the Investigator's opinion deems the participant an unsuitable candidate to receive study drugs;
• any other concurrent severe and/or uncontrolled medical condition that would, in the Investigator's judgment, contraindicate patient participation in the clinical trial or compromise compliance with the protocol.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
CDK4/6 inhibitor alone: Palbociclib (IMP)	Palbociclib	Palbociclib alone (125 mg orally (PO) per day, days 1-14)
CDK4/6 inhibitor + chemotherapy: Paclitaxel + Palbociclib	Palbociclib	Paclitaxel (80 mg/m\^2 IV, day 1, 8, 15 and 22) + Palbociclib (125 mg PO per day, days 1-21)
Chemotherapy alone: Paclitaxel	Paclitaxel	Paclitaxel alone (80 mg/m\^2 intravenously (IV), day 1, 8, 15 and 22)
CDK4/6 inhibitor + chemotherapy: Paclitaxel + Palbociclib	Paclitaxel	Paclitaxel (80 mg/m\^2 IV, day 1, 8, 15 and 22) + Palbociclib (125 mg PO per day, days 1-21)
Chemotherapy alone: Carboplatin	Carboplatin	Carboplatin alone (area under the curve (AUC) 2 IV, day 1, 8, 15 and 22)
CDK4/6 inhibitor + chemotherapy: Carboplatin + Palbociclib	Palbociclib	Carboplatin (AUC 2 IV, day 1, 8, 15 and 22) + Palbociclib (125 mg PO per day, days 1-21)
CDK4/6 inhibitor + chemotherapy: Carboplatin + Palbociclib	Carboplatin	Carboplatin (AUC 2 IV, day 1, 8, 15 and 22) + Palbociclib (125 mg PO per day, days 1-21)

Primary Outcome Measures

Name	Time	Method
Early metabolic response	Day 27 (± 3 days)	Difference in early (i.e., after three weeks of therapy, 1 cycle) metabolic response to treatment in chemotherapy-containing arms (chemotherapy ± palbociclib), as assessed by Blinded Central Review comparison of decrease in SUVmax between baseline and Day 27 (± 3 days) 18-fluoro-2-deoxy-d-glucose (18FDG) positron emission tomography - computed tomography (PET-CT). Primary analysis will include comparison between chemotherapy + palbociclib vs chemotherapy alone arms.

Secondary Outcome Measures

Name	Time	Method
Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST)	Day 27 (± 3 days)	Difference in Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST)-based peak standardized uptake value corrected for lean body mass in a spherical 1 cm3 volume of interest (SULpeak) decrease in PET-CT between chemotherapy + palbociclib vs chemotherapy alone arms.
Metabolic tumor volume (MTV) difference	Day 27 (± 3 days)	Difference in metabolic tumor volume (MTV) regression between chemotherapy + palbociclib vs chemotherapy alone arms.
Tumor diameter change	Day 27 (± 3 days)	Maximum tumor diameter change in largest continuous tumor mass based on MR imaging.
Change in tumor characteristic	Day 27 (± 3 days)	Change in tumor characteristic in Day 27 biopsy (presence of viable cancer cells).
SUVmax change	Day 27 (± 3 days)	Difference in proportion of patients with SUVmax change above the predefined cut-off of 30% between chemotherapy + palbociclib vs chemotherapy alone arms.
Treatment toxicity	Day 27 (± 3 days)	Treatment toxicity (with special attention to myeloid toxicity to explore potential myeloprotective activity): number and severity of adverse events (AEs); toxicity will be described according to ICD-10 codes and graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0).

Trial Locations

Locations (6)

Wielkopolskie Centrum Onkologii im. Marii Skłodowskiej-Curie, Oddział Onkologii Klinicznej i Immunoonkologii z Pododdziałem Dziennym; 🇵🇱 Poznań, Wielkopolskie, Poland

Dolnośląskie Centrum Onkologii we Wrocławiu, Oddział Onkologii Klinicznej/Chemioterapii, Poradnia Chemioterapii; Leczenie Nowotworów Piersi; 🇵🇱 Wrocław, Dolnośląskie, Poland

SP ZOZ Opolskie Centrum Onkologii im. Prof. Tadeusza Koszarowskiego; 🇵🇱 Opole, Opolskie, Poland

Uniwersyteckie Centrum Kliniczne, Klinika Onkologii i Radioterapii; 🇵🇱 Gdańsk, Pomorskie, Poland

Narodowy Instytut Onkologii im. Marii Skłodowskiej-Curie, Państwowy Instytut Badawczy, Oddział w Gliwicach; 🇵🇱 Gliwice, Śląskie, Poland

Narodowy Instytut Onkologii im. Marii Skłodowskiej-Curie; 🇵🇱 Warsaw, Mazowieckie, Poland