Ribociclib, Tucatinib, and Trastuzumab for the Treatment of HER2 Positive Breast Cancer

NCT05319873 | Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: 21-001819NCI-2021-11707
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

Brief Summary

This phase Ib/II trial studies the side effects and best dose of ribociclib, tucatinib, and trastuzumab for the treatment of HER2 positive breast cancer that has spread to other parts of the body (metastatic), and then compares the effect of ribociclib, tucatinib, trastuzumab with or without fulvestrant to docetaxel, carboplatin, trastuzumab, and pertuzumab (standard of care) for the treatment of early stage breast cancer before surgery (neoadjuvant therapy). Ribociclib and tucatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Trastuzumab is a form of targeted therapy because it attaches itself to specific molecules (receptors) on the surface of tumor cells, known as HER2 receptors. When trastuzumab attaches to HER2 receptors, the signals that tell the cells to grow are blocked and the tumor cell may be marked for destruction by the body's immune system. Pertuzumab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread. Estrogen can cause the growth of breast tumor cells. Fulvestrant blocks the use of estrogen by the tumor cells. Chemotherapy drugs, such as docetaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ribociclib, tucatinib, and trastuzumab with or without fulvestrant before surgery may make the tumor smaller and may reduce the amount of normal tissue that needs to be removed.

Conditions

Anatomic Stage II Breast Cancer AJCC v8; Anatomic Stage IIA Breast Cancer AJCC v8; Anatomic Stage IIB Breast Cancer AJCC v8; Anatomic Stage III Breast Cancer AJCC v8; Anatomic Stage IIIA Breast Cancer AJCC v8; Anatomic Stage IIIB Breast Cancer AJCC v8; Anatomic Stage IIIC Breast Cancer AJCC v8; Anatomic Stage IV Breast Cancer AJCC v8; Invasive Breast Carcinoma; Locally Advanced HER2-Positive Breast Carcinoma; Metastatic HER2-Positive Breast Carcinoma; Prognostic Stage IB Breast Cancer AJCC v8; Prognostic Stage II Breast Cancer AJCC v8; Prognostic Stage IIA Breast Cancer AJCC v8; Prognostic Stage IIB Breast Cancer AJCC v8; Prognostic Stage III Breast Cancer AJCC v8; Prognostic Stage IIIA Breast Cancer AJCC v8; Prognostic Stage IIIB Breast Cancer AJCC v8; Prognostic Stage IIIC Breast Cancer AJCC v8; Prognostic Stage IV Breast Cancer AJCC v8

Outcome Measures

Primary Outcomes (2)

• Maximum tolerated dose (MTD) (Phase Ib)

  Defined as the highest dose level that does not lead to unacceptable toxicity in two or more patients in a dosing level.

  During the first cycle of treatment (1 cycle = 28 days)

• Pathologic complete response (pCR) (Phase II)

  Defined as no invasive tumor in the breast or lymph nodes at the time of surgery. Response evaluable participants are defined as participants who are randomized and have receive at least one cycle of protocol therapy. The pCR rate is defined as percentage of randomized patients with a pCR in each of the treatment arms.The estimated pCR rate (and 95% confidence interval \[CIs\]) will be calculated for each experimental arm and compared to the corresponding control arm using the Cochran-Mantel-Haenszel x\^2 test, with a two-sided significance level of 5%. Absolute differences in pCR rate between study arms will be calculated, along with 95% exact confidence intervals. This will be stratified according to hormone receptor (HR) status Multivariate logistic regression will be used to control for important baseline characteristics and odds ratios with corresponding CIs will be calculated.

  Up to 30 days after last treatment dose

Secondary Outcomes (9)

• Clinical objective response rate (ORR) (Phase IB and II)

  Up to 30 days after last treatment dose

• Evaluate the pharmacokinetics of ribociclib and tucatinib when given in combination with tucatinib and trastuzumab. (Phase 1b): Area Under Curve (AUC)

  Pre-infusion and 1, 2, 3, and 6 hours after the start of the infusion

• Evaluate the pharmacokinetics of ribociclib and tucatinib when given in combination with tucatinib and trastuzumab. (Phase 1b): Elimination half-life (t½)

  Pre-infusion and 1, 2, 3, and 6 hours after the start of the infusion

• Evaluate the pharmacokinetics of ribociclib and tucatinib when given in combination with tucatinib and trastuzumab. (Phase 1b): Maximum plasma concentration (Cmax)

  Pre-infusion and 1, 2, 3, and 6 hours after the start of the infusion

• Evaluate the pharmacokinetics of ribociclib and tucatinib when given in combination with tucatinib and trastuzumab. (Phase 1b): Minimum plasma concentration

  Pre-infusion and 1, 2, 3, and 6 hours after the start of the infusion

Study Arms (4)

Phase Ib (ribociclib, tucatinib, trastuzumab)

EXPERIMENTAL

Patients receive ribociclib PO QD on days 1-21, tucatinib PO BID on days 1-28, and trastuzumab IV over 30-90 minutes every 7 days. Cycles repeat every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.

Other: Quality-of-Life Assessment; Drug: Ribociclib; Biological: Trastuzumab; Drug: Tucatinib

Phase II, Arm C (ribociclib, tucatinib, trastuzumab)

EXPERIMENTAL

Patients receive ribociclib PO QD on days 1-21, tucatinib BID on days 1-28, and trastuzumab IV over 30-90 minutes every 7 days. Cycles repeat every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

Other: Quality-of-Life Assessment; Drug: Ribociclib; Biological: Trastuzumab; Drug: Tucatinib

Phase II,Arm A(ribociclib,tucatinib, trastuzumab, fulvestrant)

EXPERIMENTAL

Patients receive ribociclib PO QD on days 1-21, tucatinib BID on days 1-28, trastuzumab IV over 30-90 minutes every 7 days and fulvestrant subcutaneously (SC) on days 1 and 15 of cycle 1 and day 1 of every subsequent cycle. Cycles repeat every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

Drug: Fulvestrant; Drug: Ribociclib; Biological: Trastuzumab; Drug: Tucatinib

Phase II,Arm B(docetaxel,carboplatin,trastuzumab,pertuzumab)

ACTIVE COMPARATOR

Patients receive docetaxel IV over 1 hour on day 1, carboplatin IV on day 1, trastuzumab IV over 30-90 minutes on day 1, and pertuzumab IV over 1 hour on day 1. Cycles repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

Drug: Carboplatin; Drug: Docetaxel; Biological: Pertuzumab; Other: Quality-of-Life Assessment; Biological: Trastuzumab

Interventions

Carboplatin DRUG

Given IV

Also known as: Blastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carboplatinum, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, Ribocarbo

Phase II,Arm B(docetaxel,carboplatin,trastuzumab,pertuzumab)

Docetaxel DRUG

Given IV

Also known as: Docecad, RP56976, Taxotere, Taxotere Injection Concentrate

Phase II,Arm B(docetaxel,carboplatin,trastuzumab,pertuzumab)

Fulvestrant DRUG

Given SC

Also known as: Faslodex, Faslodex(ICI 182,780), ICI 182,780, ICI 182780, ZD9238

Phase II,Arm A(ribociclib,tucatinib, trastuzumab, fulvestrant)

Pertuzumab BIOLOGICAL

Given IV

Also known as: 2C4, 2C4 Antibody, HS627, MoAb 2C4, Monoclonal Antibody 2C4, Omnitarg, Perjeta, Pertuzumab Biosimilar HS627, rhuMAb2C4, RO4368451

Phase II,Arm B(docetaxel,carboplatin,trastuzumab,pertuzumab)

Quality-of-Life Assessment OTHER

Ancillary Studies

Also known as: Quality of Life Assessment

Phase II, Arm C (ribociclib, tucatinib, trastuzumab); Phase II,Arm B(docetaxel,carboplatin,trastuzumab,pertuzumab); Phase Ib (ribociclib, tucatinib, trastuzumab)

Ribociclib DRUG

Given PO

Also known as: Kisqali, LEE-011, LEE011

Phase II, Arm C (ribociclib, tucatinib, trastuzumab); Phase II,Arm A(ribociclib,tucatinib, trastuzumab, fulvestrant); Phase Ib (ribociclib, tucatinib, trastuzumab)

Trastuzumab BIOLOGICAL

Given IV

Also known as: ABP 980, ALT02, Anti-c-ERB-2, Anti-c-erbB2 Monoclonal Antibody, Anti-ERB-2, Anti-erbB-2, Anti-erbB2 Monoclonal Antibody, Anti-HER2/c-erbB2 Monoclonal Antibody, Anti-p185-HER2, c-erb-2 Monoclonal Antibody, HER2 Monoclonal Antibody, Herceptin, Herceptin Biosimilar PF-05280014, Herceptin Trastuzumab Biosimilar PF-05280014, Herzuma, Kanjinti, MoAb HER2, Monoclonal Antibody c-erb-2, Monoclonal Antibody HER2, Ogivri, Ontruzant, PF-05280014, rhuMAb HER2, RO0452317, SB3, Trastuzumab Biosimilar ABP 980, Trastuzumab Biosimilar ALT02, trastuzumab biosimilar EG12014, Trastuzumab Biosimilar HLX02, Trastuzumab Biosimilar PF-05280014, Trastuzumab Biosimilar SB3, Trastuzumab Biosimilar SIBP-01, Trastuzumab-anns, Trastuzumab-dkst, Trastuzumab-dttb, Trastuzumab-pkrb, Trastuzumab-qyyp, Trazimera

Phase II, Arm C (ribociclib, tucatinib, trastuzumab); Phase II,Arm A(ribociclib,tucatinib, trastuzumab, fulvestrant); Phase II,Arm B(docetaxel,carboplatin,trastuzumab,pertuzumab); Phase Ib (ribociclib, tucatinib, trastuzumab)

Tucatinib DRUG

Given PO

Also known as: ARRY-380, Irbinitinib, ONT-380, Tukysa

Phase II, Arm C (ribociclib, tucatinib, trastuzumab); Phase II,Arm A(ribociclib,tucatinib, trastuzumab, fulvestrant); Phase Ib (ribociclib, tucatinib, trastuzumab)

Eligibility Criteria

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

You may qualify if:

• PHASE IB AND II: Patients over age of 18
• PHASE IB AND II: Available archival tissue for confirmatory central HER2 testing. Results not required prior to enrollment.
• PHASE IB AND II: Left ventricular ejection fraction (LVEF) \>= 50% based on echocardiogram or multigated acquisition (MUGA).
• PHASE IB AND II: Platelet count \>= 100,000/mm\^3 (within 7 days before enrollment)
• For Phase Ib only: Phase Ib allows for red blood cell transfusion, filgrastim (G-CSF), and hydration to meet eligibility requirements at the discretion of the investigator
• PHASE IB AND II: Hemoglobin \>= 9.0 g/dL (within 7 days before enrollment)
• For Phase Ib only: Phase Ib allows for red blood cell transfusion, G-CSF, and hydration to meet eligibility requirements at the discretion of the investigator
• PHASE IB AND II: Absolute neutrophil count (ANC) \>= 1500/mm\^3 (within 7 days before enrollment)
• For Phase Ib only: Phase Ib allows for red blood cell transfusion, G-CSF, and hydration to meet eligibility requirements at the discretion of the investigator
• PHASE IB AND II: Creatinine clearance \>= 30 mL/min as calculated using the Cockcroft-Gault equation or Serum creatinine =\< 1.5 × upper limit of normal (ULN) (within 7 days before enrollment)
• For Phase Ib only: Phase Ib allows for red blood cell transfusion, G-CSF, and hydration to meet eligibility requirements at the discretion of the investigator
• PHASE IB AND II: Alanine aminotransferase (ALT) \< 2.5 × ULN, except for patients with liver metastasis, who are only included if the ALT is \< 5 × ULN (within 7 days before enrollment)
• PHASE IB AND II: Aspartate aminotransferase (AST) \< 2.5 × ULN, except for patients with liver metastasis, who are only included if the AST is \< 5 × ULN (within 7 days before enrollment)
• PHASE IB AND II: Total bilirubin =\< 1.5 x ULN. Participants with Gilbert's syndrome with a total bilirubin =\< 2.0 times ULN and direct bilirubin within normal limits are permitted (within 7 days before enrollment)
• PHASE IB AND II: Serum Albumin \>= 2.5 g/dL (within 7 days before enrollment)

You may not qualify if:

• PHASE IB AND II: Concurrent therapy with any other non-protocol anti-cancer therapy
• PHASE IB AND II: History of any other malignancy within the past 5 years, with the exception of non-melanoma skin cancer or carcinoma-in-situ of the cervix
• PHASE IB AND II: Proteinuria estimated by urine protein: creatinine ratio \> 3.5 on a random urine sample
• PHASE IB AND II: Uncontrolled arterial hypertension despite optimal medical management
• PHASE IB AND II: Patient has known active hepatitis B virus (HBV) or hepatitis C virus (HCV), or Human immunodeficiency virus (HIV) infection (testing is not mandatory, unless required by local regulation)
• PHASE IB AND II: Uncontrolled infection; active, clinically serious infections (\> Common Terminology Criteria for Adverse Events \[CTCAE\] grade 2)
• PHASE IB AND II: Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality, including any of the following:
• History of documented myocardial infarction (MI), angina pectoris, symptomatic pericarditis, or coronary artery bypass graft (CABG) within 6 months prior to study entry
• Documented cardiomyopathy
• Left ventricular ejection fraction (LVEF) \< 50% as determined by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO)
• Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome, or any of the following:
• Risk factors for Torsades de Pointe (TdP) including uncorrected hypocalcemia, hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia
• Concomitant medication(s) with a known risk to prolong the QT interval and/or known to cause Torsades de Pointe that cannot be discontinued or replaced by safe alternative medication (e.g., within 5 half-lives or 7 days prior to starting study drug)
• Inability to determine the corrected QT using Fridericia's formula (QTcF) interval
• Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade atrioventricular (AV) block (e.g., bifascicular block, Mobitz type II and third degree AV block)

Sponsors & Collaborators

• Jonsson Comprehensive Cancer Center: lead
• Seagen Inc.: collaborator
• Novartis: collaborator

Study Sites (1)

UCLA / Jonsson Comprehensive Cancer Center

Los Angeles, California, 90095, United States

RECRUITING

MeSH Terms

Interventions

Carboplatin; Docetaxel; Fulvestrant; pertuzumab; 2C4 antibody; ribociclib; Trastuzumab; PF-05280014; Ogivri; Ontruzant; trastuzumab biosimilar HLX02; tucatinib

Intervention Hierarchy (Ancestors)

Coordination Complexes; Organic Chemicals; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Diterpenes; Terpenes; Estradiol; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Nicholas P McAndrew

  UCLA / Jonsson Comprehensive Cancer Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Monica Rocha

CONTACT

310.998-4747; mprocha@mednet.ucla.edu

Study Design

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

Model Details: Phase Ib: Sequential assignment to increasing doses of ribociclib with fixed doses of tucatinib and trastuzumab. Phase II: Randomized assignment to 3 parallel arms.

Study Record Dates

• First Submitted: March 18, 2022
• First Posted: April 8, 2022
• Study Start: April 7, 2022
• Primary Completion: April 1, 2026
• Study Completion (Estimated): April 1, 2027
• Last Updated: May 13, 2025

Record last verified: 2025-05

Locations

US (1)