An Open-Label, Phase Ib/II Clinical Trial Of Cdk 4/6 Inhibitor, Ribociclib (Lee011), In Combination With Trastuzumab Or T-Dm1 For Advanced/Metastatic Her2-Positive Breast Cancer.

NCT02657343 | Completed Phase 1 Results DMC

• 2 other identifiers: 15-530CLEE011XUS20T
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 2

Brief Summary

Participants that have breast cancer that has spread to other parts of the body, is positive for a protein called HER2, and has not responded to standard treatment. This research study is a way of gaining new knowledge about the combination of Ribociclib with other drugs as a possible treatment for this diagnosis.

Conditions

Breast Cancer

Keywords

Breast Cancer With Positive HER2

Outcome Measures

Primary Outcomes (3)

• Cohort A: Recommended Phase2 Dose (RP2D)

  Standard 3+3 phase-I design will be utilized in this trial. Briefly, a minimum of 3 evaluable patients will be entered at first dose level (=300 mg ribociclib) and T-DM1 (3.6 mg/kg IV). If 1 out of the first 3 patients enrolled experiences a dose-limiting toxicity (DLT), 3 additional patients will be enrolled to that dose level. If no more than 1 patient in 6 experiences a DLT, dose escalation of ribociclib will continue to next dose-level. If 2 or more patients at any given dose level experience a DLT, dose escalation will stop and the Recommended Phase2 Dose (RP2D) will be defined. Maximum dose-escalation of Ribociclib (LEE011) will be up to 600 mg.

  Disease was evaluated at baseline and each cycle on treatment and the end of treatment. Toxicity was evaluated each cycle on treatment, end of treatment and 30 days follow-up. Median treatment duration was 10.9 months with range 2.5 - 19.3 months.

• Cohort B: Clinical Benefit Rate (CBR)

  CBR is defined as the proportion of patients with a complete response (CR) or partial response (PR), or with stable disease (SD) at week 24 by RECIST 1.1 criteria. CBR will be reported with 90% confidence interval, adjusting for two-stage design using the method from Atkinson and Brown.

  at week 12

• Cohort C: Clinical Benefit Rate (CBR)

  CBR is defined as the proportion of patients with a complete response (CR) or partial response (PR), or with stable disease (SD) at week 24 by RECIST 1.1 criteria. CBR will be reported with 90% confidence interval, adjusting for two-stage design using the method from Atkinson and Brown.

  at week 12

Secondary Outcomes (15)

• Cohort A: Incidence of Grade 3 Treatment-Related Toxicity

  Assessed each cycle throughout treatment from time of first dose and up to day 30 post-treatment. median follow-up is 12.4 months

• Cohort A: PK Profile of Ribociclib in Combination With T-DM1.

  PK blood collection is scheduled at 0 (pre-dose), 0.5, 1, 2, 4, 6, 8, 24 hours following dosing of ribociclib.

• Cohort A: Objective Response Rate (ORR)

  Disease was evaluated radiologically at baseline and each cycle on treatment; Treatment continued until disease progression or unacceptable toxicity. Median treatment duration was 10.9 months with range 2.5 - 19.3 months.

• Cohort A: Median Progression-Free Survival (PFS)

  Disease was evaluated radiologically every cycles on treatment and in long-term follow-up every 12 weeks. Median follow-up in this study cohort was 12.4 months.

• Cohort A: Frequency of Biomarkers

  taken at any time in Cycle 2 Day 10-18.

Study Arms (3)

Cohort A: Ribociclib + T-DM1 [3+3 Design]

EXPERIMENTAL

* Ribociclib will be given orally once day (day 5-18) at a pre-determine dose for two weeks of a 21 day cycle. During dose escalation, patients received doses of ribociclib of Period 1: 300 mg (n = 3), Period 2: 400 mg (n = 3), Period 3: 500 mg (n = 3), and Period 4: 600 mg (n = 3). Maximum dose-escalation of Ribociclib will be up to 600 mg. Dose-escalation will stop if DLT exceed limit. * T-DM1 will be given as IV infusions on Day 1 of a 3 week cycle at a pre-determined dose over pre-determined period of time.

Drug: Ribociclib; Drug: T-DM1

Cohort B: Ribociclib + Trastuzumab [Phase 1b/2 Study]

EXPERIMENTAL

* Ribociclib will be given orally once day (400 mg per day on a continuous schedule) for a 21-day cycle of treatment. * Trastuzumab will be given as IV infusions over 6 mg/kg every 3 weeks.

Drug: Ribociclib; Drug: Trastuzumab

Cohort C: Ribociclib + Trastuzumab + Fulvestrant [Phase 1b/2 Study]

EXPERIMENTAL

* Ribociclib will be given orally once a day continuously for a 28-day cycle of treatment (except at Dose Level -1, when Ribociclib is given Days 1-21 of a 28 day cycle). * Trastuzumab will be given as IV infusions over a pre-determined period of time and dose. Fulvestrant will be dosed approximately every 28 days as per standard of care.

Drug: Ribociclib; Drug: Trastuzumab; Drug: Fulvestrant

Interventions

Ribociclib DRUG

Also known as: LEE-011

Cohort A: Ribociclib + T-DM1 [3+3 Design]; Cohort B: Ribociclib + Trastuzumab [Phase 1b/2 Study]; Cohort C: Ribociclib + Trastuzumab + Fulvestrant [Phase 1b/2 Study]

T-DM1 DRUG

Also known as: Kadcyla

Cohort A: Ribociclib + T-DM1 [3+3 Design]

Trastuzumab DRUG

Also known as: Herceptin

Cohort B: Ribociclib + Trastuzumab [Phase 1b/2 Study]; Cohort C: Ribociclib + Trastuzumab + Fulvestrant [Phase 1b/2 Study]

Fulvestrant DRUG

Also known as: Faslodex

Cohort C: Ribociclib + Trastuzumab + Fulvestrant [Phase 1b/2 Study]

Eligibility Criteria

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

You may qualify if:

• Participants must have histologically confirmed invasive breast cancer, with locally advanced or metastatic disease. Patients without pathologic confirmation of metastatic disease should have unequivocal evidence of metastasis from physical examination or radiologic evaluation.
• The primary tumor, and/or metastasis must have been tested for ER, PR and HER 2, and be HER2 positive as defined by the 2013 ASCO-CAP guidelines.
• Measureable disease by RECIST 1.1 (at least one lesion that can be accurately measured in at least one dimension \> 20mm with conventional imaging techniques or \> 10mm with spiral CT or MRI) or evaluable disease. Bone lesions (blastic, lytic, or mixed) in the absence of measurable disease as defined above are also acceptable.
• Prior treatment
• Cohort A:
• Prior treatment with at least one regimen containing Trastuzumab and taxane.
• No prior treatment with T-DM1 that was discontinued due to disease progression or toxicity.
• No more than 4 prior lines of therapy in the metastatic setting.
• Cohort B:
• Must have received prior Trastuzumab, pertuzumab, and T-DM1 in neo-adjuvant, adjuvant, or metastatic setting.
• No limit on prior lines of therapies.
• Cohort C:
• Must have received prior Trastuzumab, pertuzumab, and T-DM1 in neo=adjuvant, adjuvant, or metastatic setting.
• Maximum of 5 prior lines of therapy for metastatic disease.
• Prior treatment with fulvestrant is permitted.

You may not qualify if:

• Participants who have had chemotherapy within 14 days prior registration or those who have not recovered from all toxicities related to prior anticancer therapies to NCI-CTCAE version 4.03 Grade ≤1 (Exception to this criterion: patients with any grade of alopecia are allowed to enter the study). There is no washout period required for Trastuzumab.
• Participants who have received radiotherapy ≤ 2 weeks prior to starting study drug, and who have not recovered to grade 1 or better from related side effects of such therapy (except alopecia and neuropathy) and/or in whom ≥ 25% of the bone marrow was irradiated.
• Participants who have previously received a CDK 4/6 inhibitor.
• Participants with central nervous system (CNS) involvement unless they meet ALL of the following criteria:
• At least 4 weeks from prior therapy completion (including radiation and/or surgery) to starting the study treatment
• Clinically stable CNS tumor at the time of screening and not receiving steroids and/or enzyme-inducing anti-epileptic medications for brain metastases.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to ribociclib, T-DM1 (Cohort A) and/or Trastuzumab (Cohort B).
• In general, the use of any concomitant medication deemed necessary for the care of the patient is permitted in this study, except as specifically prohibited below. Combination administration of study drugs could result in drug-drug interactions (DDI) that could potentially lead to reduced activity or enhanced toxicity of the concomitant medication and/or Ribociclib.
• Patient is currently receiving any of the following medications and cannot discontinue use within 7 days prior to starting study drug (see (Tables 1 and 2, Appendix B for details):
• Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit hybrids, pummelos, star-fruit, and Seville oranges
• That have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5
• Herbal preparations/medications, dietary supplements.
• The list provided here (and in Tables 1 and 2, Appendix B) is not comprehensive and is only meant to be used as a guide. The list is based on the Oncology Clinical Pharmacology Drug-Drug Interaction Database (release date: 29 Oct 2012), which was compiled from the Indiana University School of Medicine's P450 Drug Interaction Table.
• http://medicine.iupui.edu/clinpharm/ddis/main-table/) and supplemented with the FDA Draft Guidance for Industry, Drug Interaction Studies - Study Design, Data Analysis, and Implications for Dosing and Labeling (February 2012) (http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm292362.pdf), and the University of Washington's Drug Interaction Database (http://www.druginteractioninfo.org/). For current lists of medications that may cause QT prolongation and/or torsades de pointes (TdP), refer to the CredibleMeds® website (https://crediblemeds.org/).
• Participants who have any other concurrent severe and/or uncontrolled medical condition that would, in the investigator's judgment, cause unacceptable safety risks, contraindicate patient participation in the clinical trial or compromise compliance with the protocol (e.g. chronic pancreatitis, chronic active hepatitis, active untreated or uncontrolled fungal, bacterial or viral infections, etc.).

Sponsors & Collaborators

• Dana-Farber Cancer Institute: lead
• Novartis: collaborator

Study Sites (2)

Massacusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Related Publications (1)

• Goel S, Pernas S, Tan-Wasielewski Z, Barry WT, Bardia A, Rees R, Andrews C, Tahara RK, Trippa L, Mayer EL, Winer EP, Spring LM, Tolaney SM. Ribociclib Plus Trastuzumab in Advanced HER2-Positive Breast Cancer: Results of a Phase 1b/2 Trial. Clin Breast Cancer. 2019 Dec;19(6):399-404. doi: 10.1016/j.clbc.2019.05.010. Epub 2019 May 30.

  PMID: 31235441 DERIVED

MeSH Terms

Conditions

Breast Neoplasms

Interventions

ribociclib; Ado-Trastuzumab Emtansine; Trastuzumab; Fulvestrant

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Maytansine; Macrolides; Lactones; Organic Chemicals; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Estradiol; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Results Point of Contact

• Title: Sara Tolaney, MD, MPH
• Organization: Dana-Farber Cancer Institute

Sara_Tolaney@dfci.harvard.edu

(877) 442-3324

Study Officials

• Sara Tolaney, MD MPH

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Sara Tolaney MD, MPH

Study Record Dates

• First Submitted: January 13, 2016
• First Posted: January 15, 2016
• Study Start: March 9, 2016
• Primary Completion: August 27, 2020
• Study Completion: June 30, 2022
• Last Updated: August 1, 2022
• Results First Posted: June 3, 2022

Record last verified: 2022-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)