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Breast CancerPhase 1NCT01857193

Phase Ib Trial of LEE011 With Everolimus (RAD001) and Exemestane in the Treatment of Hormone Receptor Positive HER2 Negative Advanced Breast Cancer

A Phase 1 study testing ribociclib (LEE011), Exemestane and Everolimus (RAD001) in people with Breast Cancer, run by Novartis Pharmaceuticals at 13 sites in 5 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

Dose Escalation part of the study: To estimate the MTD(s) and/ or RP2D of LEE011 in combination with everolimus + exemestane, and LEE011 in combination with exemestane, and to characterize the safety and tolerability of the combinations of everolimus + exemestane + LEE011 and LEE011 + exemestane in patients with ER+… Read more about this study

Who is it for?
Ages 18 years and older, women only
Conditions the study is for
Breast Cancer
What is being tested?
ribociclib (LEE011), Exemestane and Everolimus (RAD001)
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
132 participants
Where
13 sitesin 5 countries
Study dates
6 Sep 2013to 16 Apr 2020
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • Women only
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Adult women (≥ 18 years of age) with metastatic or locally advanced breast cancer
  • Histological or cytological confirmation of ER+ breast cancer in dose escalation and HR+ breast cancer in dose expansion
  • A representative tumor specimen must be available for molecular testing.
  • Postmenopausal women. Postmenopausal status is defined either by:
  • Age ≥ 18 with prior bilateral oophorectomy
  • Age ≥ 60 years
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  • Age <60 years with amenorrhea for at least 12 months and both follicle-stimulating hormone (FSH) and estradiol levels are in postmenopausal range (according to the local laboratory)
  • Recurrence while on, or within 12 months of end of adjuvant treatment with letrozole or anastrozole, or
  • Progression while on, or within one month of end of letrozole or anastrozole treatment for locally advanced or metastatic breast cancer.
  • Patients must have:
  • Measurable disease*: At least one lesion that can be accurately measured in at least one dimension ≥ 20 mm with conventional imaging techniques or ≥ 10 mm with spiral CT or MRI or
  • Bone lesions: lytic or mixed (lytic + sclerotic) in the absence of measurable disease as defined above.
  • ECOG Performance Status 0-1.
  • Fasting serum cholesterol ≤ 300 mg/dl or 7.75 mmol/L and fasting triglycerides ≤ 2.5 × ULN. In case one or both of these thresholds are exceeded, the patient can only be included after initiation of statin therapy and when the above mentioned values have been achieved
  • Standard 12-lead ECG values defined as the mean of the triplicate ECGs and assessed by the central laboratory.
  • QTcF interval at screening < 450 msec (using Fridericia's correction).
  • Resting heart rate 50-90 bpm

Who cannot join

  • HER2-overexpressing patients by local laboratory testing (IHC 3+ staining or in situ hybridization positive).
  • Patients who received more than one chemotherapy line for advanced breast cancer.
  • Previous treatment with exemestane or mTOR inhibitors* (Note:
  • Patients with disease refractory to prior LEE011 are excluded for dose expansion Group 3 only).
  • History of brain or other CNS metastases.
  • Clinically significant, uncontrolled heart disease and/or recent cardiac repolarization abnormality including any of the following:
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  • History of 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 scan (MUGA) or echocardiogram (ECHO)
  • Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome, and etc.
  • Clinically significant cardiac arrhythmias, complete left bundle branch block, high-grade AV block
  • Systolic Blood Pressure (SBP) >160 or <90 mmHg
  • Patients who are currently receiving treatment with agents that are known to cause QTc prolongation in humans
  • Patients who are currently receiving treatment (within 7 days prior to starting study treatment) with strong and moderate inhibitors or inducers of CYP3A4/5, substrates of CYP3A4/5 with a narrow therapeutic index or Herbal preparations/medications (Refer to Section 6.4 and Appendix 3)
  • Inclusion Criteria Exceptions for Phase Ib Dose Expansion patients:
  • Dose Expansion part of the study has 3 groups, following are the Inclusion Criteria exceptions for these 3 groups
  • Group 1 - Patients must not have received prior treatment with any CDK4/6 inhibitors
  • Group 2 - Patients must have disease progression while on or within one month after CDK4/6 inhibitor based therapy
  • Group 3 - Patients must have disease progression while on or within one month after CDK4/6 inhibitor based therapy (except those patients who received prior LEE011 based therapy).
  • Other protocol-defined Inclusion/Exclusion may apply.

Trial locations and contacts

13 sites in 5 countries.

13 sites in 5 countries

United States8 sites

  • Massachusetts General Hospital Onc Dept

    Boston, Massachusetts, 02114

  • Karmanos Cancer Institute Dept of Onc

    Detroit, Michigan, 48201

  • Highlands Oncology Group

    Fayetteville, Arkansas, 72703

  • University of Texas MD Anderson Cancer Center Onc Dept

    Houston, Texas, 77030

  • Sylvester Comprehensive Cancer Center Main Center

    Miami, Florida, 33136

  • Memorial Sloan Kettering Oncology Dept.

    New York, New York, 10017

  • Oregon Health and Science University SC-5

    Portland, Oregon, 97239

  • Northwest Medical Specialties

    Tacoma, Washington, 98405

Other trials in United States

Spain2 sites

  • Novartis Investigative Site

    Barcelona, Catalonia, 08035

  • Novartis Investigative Site

    L'Hospitalet de Llobregat, Catalonia, 08907

Other trials in Spain

Belgium1 site

  • Novartis Investigative Site

    Wilrijk, 2610

Other trials in Belgium

France1 site

  • Novartis Investigative Site

    Saint-Herblain, 44805

Other trials in France

Hong Kong1 site

  • Novartis Investigative Site

    Hong Kong

Other trials in Hong Kong

About this study

Official title: A Phase Ib Trial of LEE011 in Combination With Everolimus (RAD001) and Exemestane in the Treatment of Postmenopausal Women With Hormone Receptor Positive, HER2 Negative Locally Advanced or Metastatic Breast Cancer

Dose Escalation part of the study: To estimate the MTD(s) and/ or RP2D of LEE011 in combination with everolimus + exemestane, and LEE011 in combination with exemestane, and to characterize the safety and tolerability of the combinations of everolimus + exemestane + LEE011 and LEE011 + exemestane in patients with ER+ HER2- advanced breast cancer

Dose Expansion part of the study: To characterize the safety and tolerability of the triplet combination of LEE011 + everolimus + exemestane in patients naïve or refractory to CDK4/6 inhibitor based therapy, and the safety and tolerability of the doublet combination of LEE011 + exemestane in patients refractory to CDK4/6 inhibitor based therapy (except patients treated with prior LEE011 are not allowed in Group 3).

Read the detailed description

The primary purpose of the phase Ib part of this study is to determine the maximum tolerated dose(s) (MTD(s)) and/or recommended phase II dose (RP2D) of LEE011 + everolimus + exemestane in patients with ER+ Her2- advanced breast cancer. This part of the study will also assess safety, tolerability, and PK of the LEE011 + exemestane, LEE011 + everolimus + exemestane combinations.

The Dose Expansion part of the study will evaluate the triple combination of LEE011 + everolimus + exemestane and the double combination of LEE011 + exemestane for safety and tolerability.

Conditions
Breast Cancer
Being tested
ribociclib (LEE011), Exemestane, Everolimus (RAD001)
Keywords
Open label, dose escalation, ER+, LEE011, CDK4/6, everolimus, advanced breast cancer, mTOR, HR positive, HER2 negative
Medical subject headings
Breast Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • ribociclib (LEE011)Drug

    Also called LEE011

    LEE011 is taken orally once per day for 21 days of each 28 day cycle. LEE011 comes in 50 mg and 200 mg capsules.

  • ExemestaneDrug

    Exemestane is taken orally once per day. Exemestane comes in 25 mg tablets.

  • Everolimus (RAD001)Drug

    Also called RAD001

    Everolimus is taken orally once per day. Everolimus comes in 1 mg, 2.5 mg, 5mg, and 7.5 mg tablets

Study groups in NCT01857193
Study groupRoleWhat they receive
L-R-E armExperimentalParticipants who took ribociclib (LEE011), everolimus (RAD001) and exemestane triple combination
Receives: Drug: ribociclib (LEE011); Drug: Exemestane; Drug: Everolimus (RAD001)
L-E armExperimentalParticipants who ribociclib (LEE011) and exemestane double combination
Receives: Drug: ribociclib (LEE011); Drug: Exemestane

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Dose Escalation: Incidence of Dose Limiting Toxicity (DLT)

    DLT is defined as treatment-related toxicity (classified according Common Toxicity Criteria for Adverse Events (CTCAE) Version 4) occurring during the first 28 treatment days and meeting specific protocol-predefined criteria.

    Measured: At the end of Cycle 1 (each cycle is 28 days)

  2. Dose Expansion: Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)

    Adverse events were collected for approximately 4.5 years for dose expansion including the 30 days safety follow-up period.

    Measured: Approximately 4.5 years after FPFV

Secondary outcomes (13)

  1. Dose Escalation: Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)

    Adverse events were collected for approximately 6.5 years for dose escalation including the 30 days safety follow-up period.

    Measured: Approximately 6.5 years after FPFV

  2. Dose Escalation and Expansion: Overall Response Rate (ORR)

    Overall Response Rate (ORR) is defined as the proportion of participants with a best overall response of complete response or partial response.

    Measured: Approximately 6.5 years for Dose Escalation and 4.5 years for Dose Espansion after FPFV

  3. Dose Escalation and Expansion: Disease Control Rate (DCR)

    Disease Control Rate (DCR) is the proportion of patients with a best overall response of Complete Response or Partial Response or Stable Disease.

    Measured: Approximately 6.5 years for Dose Escalation and 4.5 years for Dose expansion after FPFV

  4. Dose Escalation and Expansion: Clinical Benefit Rate (CBR)

    Clinical Benefit Rate (CBR) is the Complete Response, Partial Response, or Stable Disease lasting 24 weeks or longer

    Measured: Approximately 6.5 years for Dose Escalation and 4.5 years for Dose Espansion after FPFV

  5. Dose Expansion: Duration of Response (DOR)

    Duration of Response (DOR) is calculated as the time from the date of first documented response (complete response (CR) or partial response (PR)) to the first documented date of progression or death due to underlying cancer. The DOR is not applicable as none of the patients in the expansion treatment groups (triplet treatment naive, triplet treatment refractory and doublet treatment refractory) had a CR or PR

    Measured: Approximately 4.5 years for dose expansion after FPFV

  6. Dose Expansion: Progression Free Survival (PFS)

    Progression Free Survival (PFS) is defined as the time from date of randomization/start of treatment to the date of event defined as the first documented progression or death due to any cause. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment.

    Measured: Approximately 4.5 years after FPFV

  7. Dose Escalation: Pharmacokinetics (PK) parameter: AUC0-24h at Day 1 of Cycle 1

    AUC0-24h is the area under the drug concentration-time curve during a dosing interval (mass x time x volume-1).

    Measured: 6 Cycles of treatment (28 day cycles): Cycle 1 Day 1

  8. Dose Escalation: Pharmacokinetics (PK) parameter: AUC0-24h at at Day 15 of Cycle 1

    AUC0-24h is the area under the drug concentration-time curve during a dosing interval (mass x time x volume-1).

    Measured: 6 Cycles of treatment (28 day cycles): Cycle 1 Day 15

  9. Dose Escalation: Pharmacokinetics (PK) parameter: Cmax at Day 1 of Cycle 1

    Cmax is the maximum observed drug concentration after drug administration (mass x volume-1).

    Measured: 6 Cycles of treatment (28 day cycles): Cycle 1 Day 1

  10. Dose Escalation: Pharmacokinetics (PK) parameter: Cmax at Day 15 of Cycle 1

    Cmax is the maximum observed drug concentration after drug administration (mass x volume-1).

    Measured: 6 Cycles of treatment (28 day cycles): Cycle 1 Day 15

  11. Dose Escalation: Pharmacokinetics (PK) parameter: Tmax at Day 1 of Cycle 1

    Tmax is the time to reach maximum plasma/blood/serum drug concentration (time).

    Measured: 6 Cycles of treatment (28 day cycles): Cycle 1 Day 1

  12. Dose Escalation: Pharmacokinetics (PK) parameter: Tmax at Day 15 of Cycle 1

    Tmax is the time to reach maximum plasma/blood/serum drug concentration (time).

    Measured: 6 Cycles of treatment (28 day cycles): Cycle 15 Day 1

  13. Dose Escalation: Pharmacokinetics (PK) parameter: Racc at Day 15 of Cycle 1

    Racc is the accumulation ratio calculated as AUCtau,ss / AUCtau,sd

    Measured: 6 Cycles of treatment (28 day cycles): Cycle 15 Day 1

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted20 May 2013 (estimated)
  2. Study start6 Sep 2013
  3. Primary completion14 Mar 2018
  4. Study completion16 Apr 2020

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
132 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01857193
Sponsor's protocol ID
CLEE011X2106
Status last verified
Apr 2021
First submitted
16 May 2013
Last updated
13 Apr 2021
Results posted
No
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing ribociclib (LEE011), Exemestane and Everolimus (RAD001) in people with Breast Cancer, run by Novartis Pharmaceuticals at 13 sites in 5 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 17 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 13 Apr 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 13 sites in United States, Spain, Belgium, France, Hong Kong. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Dose Escalation: Incidence of Dose Limiting Toxicity (DLT) (time frame: At the end of Cycle 1 (each cycle is 28 days)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01857193.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Apr 2021.

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