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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Triple Negative Breast Neoplasms
• Intervention / Treatment: Drug: Palbociclib; Drug: Paclitaxel; Drug: Carboplatin

• Study Type: Interventional
• Enrollment (Anticipated): 126
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Elżbieta Senkus-Konefka, MD, PhD; Phone Number: 0048 58 584 4482; Email: elzbieta.senkus-konefka@gumed.edu.pl
• Study Contact Backup: Name: Monika Puchowska, MSc; Phone Number: 0048 58 349 1885; Email: monika.puchowska@gumed.edu.pl

Study Locations

• Poland
  • Dolnośląskie
    • Wrocław, Dolnośląskie, Poland, 53-413
      • Dolnośląskie Centrum Onkologii we Wrocławiu, Oddział Onkologii Klinicznej/Chemioterapii, Poradnia Chemioterapii; Leczenie Nowotworów Piersi
      • Contact: Aleksandra Łacko, MD, PhD; Phone Number: 0048 71 368 94 83; Email: aleksandra.lacko@umed.wroc.pl
      • Principal Investigator: Aleksandra Łacko, MD, PhD
  • Mazowieckie
    • Warsaw, Mazowieckie, Poland, 22 546 20 00
      • Narodowy Instytut Onkologii im. Marii Skłodowskiej-Curie
      • Contact: Agnieszka Jagiełło-Gruszfeld, MD, PhD; Phone Number: 0048 22 546 20 00; Email: agnieszka.jagiello-gruszfeld@gmail.com
      • Principal Investigator: Agnieszka Jagiełło-Gruszfeld, MD, PhD
  • Opolskie
    • Opole, Opolskie, Poland, 45-061
      • SP ZOZ Opolskie Centrum Onkologii im. prof. Tadeusza Koszarowskiego
      • Contact: Barbara Stefania Radecka, MD, PhD; Phone Number: 0048 77 441 60 01; Email: brad@onkologia.opole.pl
      • Principal Investigator: Barbara Stefania Radecka, MD, PhD
  • Pomorskie
    • Gdańsk, Pomorskie, Poland, 80-952
      • Uniwersyteckie Centrum Kliniczne, Klinika Onkologii i Radioterapii
      • Principal Investigator: Elżbieta Senkus-Konefka, MD, PhD
  • Wielkopolskie
    • Poznań, Wielkopolskie, Poland, 61 885 05 57
      • Wielkopolskie Centrum Onkologii im. Marii Skłodowskiej-Curie, Oddział Onkologii Klinicznej i Immunoonkologii z Pododdziałem Dziennym
      • Contact: Maria Małgorzata Litwiniuk, MD, PhD; Phone Number: 0048 61 885 05 57; Email: maria.litwiniuk@wco.pl
      • Principal Investigator: Maria Małgorzata Litwiniuk, MD, PhD
  • Śląskie
    • Gliwice, Śląskie, Poland, 44-102
      • Narodowy Instytut Onkologii im. Marii Skłodowskiej-Curie, Państwowy Instytut Badawczy, Oddział w Gliwicach
      • Contact: Michał Jarząb, MD, PhD; Phone Number: 0048 32 278 88 86; Email: michal.jarzab@io.gliwice.pl
      • Principal Investigator: Michał Jarząb, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CDK4/6 inhibitor alone: Palbociclib (IMP); Palbociclib alone (125 mg orally (PO) per day, days 1-14)	Drug: Palbociclib; CDK4/6 inhibitor; Other Names: Ibrance
Active Comparator: Chemotherapy alone: Paclitaxel; Paclitaxel alone (80 mg/m^2 intravenously (IV), day 1, 8, 15 and 22)	Drug: Paclitaxel; Chemotherapy
Experimental: CDK4/6 inhibitor + chemotherapy: Paclitaxel + Palbociclib; Paclitaxel (80 mg/m^2 IV, day 1, 8, 15 and 22) + Palbociclib (125 mg PO per day, days 1-21)	Drug: Palbociclib; CDK4/6 inhibitor; Other Names: Ibrance; Drug: Paclitaxel; Chemotherapy
Active Comparator: Chemotherapy alone: Carboplatin; Carboplatin alone (area under the curve (AUC) 2 IV, day 1, 8, 15 and 22)	Drug: Carboplatin; Chemotherapy
Experimental: CDK4/6 inhibitor + chemotherapy: Carboplatin + Palbociclib; Carboplatin (AUC 2 IV, day 1, 8, 15 and 22) + Palbociclib (125 mg PO per day, days 1-21)	Drug: Palbociclib; CDK4/6 inhibitor; Other Names: Ibrance; Drug: Carboplatin; Chemotherapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Early metabolic response	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.	Day 27 (± 3 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
SUVmax change	Difference in proportion of patients with SUVmax change above the predefined cut-off of 30% between chemotherapy + palbociclib vs chemotherapy alone arms.	Day 27 (± 3 days)
Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST)	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.	Day 27 (± 3 days)
Metabolic tumor volume (MTV) difference	Difference in metabolic tumor volume (MTV) regression between chemotherapy + palbociclib vs chemotherapy alone arms.	Day 27 (± 3 days)
Tumor diameter change	Maximum tumor diameter change in largest continuous tumor mass based on MR imaging.	Day 27 (± 3 days)
Change in tumor characteristic	Change in tumor characteristic in Day 27 biopsy (presence of viable cancer cells).	Day 27 (± 3 days)
Treatment toxicity	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).	Day 27 (± 3 days)

Collaborators and Investigators

• Sponsor: Medical University of Gdansk

Study record dates

Study Major Dates

• Study Start (Anticipated): January 1, 2022
• Primary Completion (Anticipated): January 1, 2025
• Study Completion (Anticipated): December 6, 2026

Study Registration Dates

• First Submitted: September 23, 2021
• First Submitted That Met QC Criteria: October 4, 2021
• First Posted (Actual): October 5, 2021

Study Record Updates

• Last Update Posted (Actual): October 5, 2021
• Last Update Submitted That Met QC Criteria: October 4, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Triple Negative Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Protein Kinase Inhibitors; Carboplatin; Paclitaxel; Palbociclib
• Other Study ID Numbers: NBK 171/1/2021; 2021-001556-33 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No