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Breast Diseases

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Fulvestrant

Ado-Trastuzumab Emtansine

Antineoplastic Agents, Immunological

Antineoplastic Agents, Hormonal

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Estrogen Antagonists

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Hormones

Hormone Antagonists

* 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.

* 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.

* 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.

Ribociclib

T-DM1

Sara Tolaney, MD MPH

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.

This research study is a Phase Ib/II clinical trial, which tests the safety of an investigational intervention and also tries to define the appropriate dose of the investigational intervention to use for further studies.

Ribociclib is a drug that is designed to block certain proteins called Cyclin-Dependent Kinases (CDKs) that are required for cells to divide. These proteins may also control the ability of certain cancers to grow.

In this research study, there will be 3 separate cohorts that are looking for the safe and tolerated dose of ribociclib that can be given in combination with other HER2 directed therapy. One cohort will be looking at the safety of ribociclib in combination with trastuzumab emtansine (T-DM1). T-DM1 is a standard treatment for patients with HER2-positive breast cancer. One Cohort will be looking at the safety of ribociclib in combination with trastuzumab (Herceptin), which is a standard treatment for patients with HER2-positive breast cancer. The last cohort will be looking at the safety of ribociclib in combination with trastuzumab (Herceptin) and fulvestrant (Faslodex) for ER-positive and HER2-positive breast cancer. These are both standard treatments for this type of breast cancer.

The FDA (the U.S. Food and Drug Administration) has not approved Ribociclib as a treatment for any disease.

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.

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.

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.

All grade 4 adverse events (AE) with treatment attribution of possibly, probably or definite based on CTCAEv4 as reported on case report forms were counted. Incidence is the number of patients experiencing at least one treatment-related grade 4 AE of any type during the time of observation.

pharmacokinetics (PK) tudies demonstrated dose-related inhibition of Rb phosphorylation in tumors, with continuous dosing over at least 3-5 days being required to achieve optimal target inhibition.

Objective response rate(ORR) was defined as the portion of patients with complete response or partial response by RECIST 1.1 criteria.

Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

Progression-free survival based on the Kaplan-Meier method is defined as the duration of time from study entry to documented disease progression (PD) or death. Per RECIST 1.1 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions.

Optional tumor samples (if safely accessible and feasible) will be taken pre- and post-treatment in order to assess dose-dependent target modulation.

OS based on the Kaplan-Meier method is defined as the time from study entry to death or censored at date last known alive.

all grade 4 adverse events (AE) with treatment attribution of possibly, probably or definite based on CTCAEv4 as reported on case report forms were counted. Incidence is the number of patients experiencing at least one treatment-related grade 4 AE of any type during the time of observation.

Novartis

Dana-Farber Cancer Institute

Sara Tolaney MD, MPH

Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.

* 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 300 mg (n = 3) 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.

Cohort A: Ribociclib + T-DM1 [Dose 1: 300mg]

* 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 400 mg (n = 3) 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.

Cohort A: Ribociclib + T-DM1 [Dose 2: 400mg]

* 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 500 mg (n = 3) 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.

Cohort A: Ribociclib + T-DM1 [Dose 3: 500mg]

* 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 600 mg (n = 3) 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.

Cohort A: Ribociclib + T-DM1 [Dose 4: 600mg]

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

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

Total

Age, Continuous

Sex: Female, Male

White

Other

Race/Ethnicity, Customized

United States

Region of Enrollment

Sara Tolaney, MD, MPH

* 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 300 mg (n = 3), 400 mg (n = 3), 500 mg (n = 3), and 600 mg (n = 3).
* 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.

Cohort A: Ribociclib + T-DM1

Cohort A: Recommended Phase2 Dose (RP2D)

Ribociclib will be given orally once day continuously for a 21-day cycle of treatment (except at Dose Level -2, when Ribociclib is given Days 1-14 of a 21 day cycle). Trastuzumab will be given as IV infusions over a pre-determined period of time and dose.

Cohort B: Ribociclib + Trastuzumab

Cohort B: Clinical Benefit Rate (CBR)

Cohort C: Ribociclib + Trastuzumab + Fulvestrant

Cohort C: Clinical Benefit Rate (CBR)

neutropenia

leukopenia

anemia

lymphopenia

thrombocytopenia

febrile neutropenia

Cohort A: Incidence of Grade 3 Treatment-Related Toxicity

0 patient data collected because study plan changed

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

Cohort A: Objective Response Rate (ORR)

Cohort A: Median Progression-Free Survival (PFS)

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 300 mg (n = 3), 400 mg (n = 3), 500 mg (n = 3), and 600 mg (n = 3).

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.

biopsy data not collected because study plan changed

Cohort A: Frequency of Biomarkers

* Ribociclib will be given orally once day (400 mg per day on a continuous schedule) for a 21-day cycle of treatment (except at Dose Level -2, when Ribociclib is given Days 1-14 of a 21 day cycle).
* Trastuzumab will be given as IV infusions over 6 mg/kg every 3 weeks.

Cohort B: Objective Response Rate (ORR)

Cohort B: Median Progression-Free Survival (PFS)

Cohort B: Overall Survival (OS)

fatigue

pain

Cohort B: Incidence of Grade 3 Treatment-Related Toxicity

biopsy will not be done because the study plan changed

Cohort B: Frequencies Of Biomarkers

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.

data not collected because no patient enrolled

Cohort C: Objective Response Rate (ORR)

data not collected because no patients enrolled

Cohort C: Median Progression-Free Survival (PFS)

Cohort C: Overall Survival (OS)

Cohort C: Incidence of Grade 3 Treatment-Related Toxicity

Cohort C: Frequency of Potential Biomarkers

* 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 300 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.

Cohort A: Ribociclib + T-DM1Cohort A: Ribociclib + T-DM1 [Dose 1: 300mg]

* 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 400 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.

Cohort A: Ribociclib + T-DM1Cohort A: Ribociclib + T-DM1 [Dose 2: 400mg]

* 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 500 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.

Cohort A: Ribociclib + T-DM1Cohort A: Ribociclib + T-DM1 [Dose: 500 mg]

* 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 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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
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	Breast Cancer	Ribociclib T-DM1 Trastuzumab Fulvestrant	18 Years -	Dana-Farber Cancer Institute
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	Breast Cancer	Ribociclib T-DM1 Trastuzumab Fulvestrant	18 Years -	Dana-Farber Cancer Institute

Spots Global Cancer Trial Database for breast cancer with positive her2