HER2-positive Breast CancerPhase 1/2NCT03913234
Phase IB & II Study of Ribociclib With Trastuzumab Plus Letrozole in Postmenopausal HR+, HER2+ Advanced Breast Cancer Patients
A Phase 1/2 study testing Ribociclib, Trastuzumab, Letrozole in people with HER2-positive Breast Cancer and Postmenopausal, run by Yonsei University at 1 site in South Korea.
Trial summary
Survival benefit and quality of life are two key elements that should be kept in mind in the treatment of metastatic breast cancer. In this regards, endocrine therapy (ET) is strongly recommended in hormone receptor (HR) positive patients unless there is visceral crisis even though there is no concrete evidence that… Read more about this study
- Who is it for?
- Ages 19 years and older, women only
- Conditions the study is for
- HER2-positive Breast Cancer, Postmenopausal, Metastatic Breast Cancer
- What is being tested?
- Ribociclib, Trastuzumab, Letrozole
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 95 participants
- Where
- 1 siteSouth Korea
- Study dates
- 10 Jun 2019to 30 Oct 2023
- Phase
- Phase 1/2
- 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 19 years and older
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patients aged ≥19 years
- Women with advanced (loco-regionally recurrent or metastatic) breast cancer not amenable for curative therapy
- Histologically and/or cytologically confirmed estrogen receptor positive and/or progesterone receptor positive breast cancer
- HER2 positive breast cancer (IHC 3+ or IHC 2+ and FISH, SISH or CISH+)
- Postmenopausal patient defined as either one of the following.
- Prior bilateral ovariectomy
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- Age ≥ 60 years old
- Age <60 years and amenorrhea over 12 months (without chemotherapy, tamoxifen, toremifene or ovarian inhibition), FSH and estradiol are in the postmenopausal range according to local normal range
- Patients who were not previously treated with systemic treatment for advanced / metastatic breast cancer
- ECOG performance status 0 or 1
- Measurable or evaluable lesion according to RECIST v1.1
- Normal organ function defined as
- ANC (absolute neutrophil count) ≥ 1.5 × 109/L
- Platelet ≥ 100 × 109/L
- Serum Hb ≥ 9.0 g/dL
- INR ≤1.5
- Serum creatinine ≤ 1.5 X ULN
- ALT \& ALT < 2.5 X ULN (in the absence of liver metastasis) or ALT \& ALT < 5 X ULN (with liver metastasis)
- Total serum bilirubin < 1.5 X ULN
- Left Ventricular Ejection Fraction (LVEF) within normal range
- Voluntary agreement on clinical trials
Who cannot join
- Patients who have previously received CDK4 / 6 inhibitors or who have received other systemic treatments for advanced / metastatic breast cancer (Previous neo-adjuvant of adjuvant trastuzumab or aromatase inhibitor is not allowed, unless
- Disease free interval was more than 12 months from the last dose of adjuvant trastuzumab or
- Adjuvant aromatase inhibitor was administered more than 2 years)
- Inflammatory breast cancer
- Central nervous system metastasis
- Active cardiac disease or a history of cardiac dysfunction including any of the following (Congestive heart failure within 6 months, history of myocardial infarction, unstable angina pectoris, or QTc prolongation on electrocardiogram)
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- Gastrointestinal absorption disorders that interfere with drug absorption
- Patients who is currently receiving medications that can prolong QT intervals (QTc>450msec) on ECG or that can cause torsades de pointes
- Patients with severe visceral metastasis on enrolment who are not indicated with hormone treatment
- Serious surgical treatment within 14 days prior to study treatment
- Radiotherapy within 21 days prior to study treatment
- Serious medical comorbidities
- Concurrent malignancy or malignancy within 3 years of study participation, with the exception of adequately treated, basal or squamous cell carcinoma, non-melanomatous skin cancer or curatively resected cervical cancer.
Trial locations and contacts
1 site in 1 country.
South Korea1 site, 1 recruiting
- Recruiting
Yonsei Cancer Center at Yonsei University Health System
Seoul, 03722
Joo Hyuk Sohn, MD, PhD, 82-2-2228-8135, oncosohn@yuhs.ac
About this study
Survival benefit and quality of life are two key elements that should be kept in mind in the treatment of metastatic breast cancer. In this regards, endocrine therapy (ET) is strongly recommended in hormone receptor (HR) positive patients unless there is visceral crisis even though there is no concrete evidence that it is better than chemotherapy in terms of survival.
HER2 positive breast cancer is a subtype of breast cancer that showed the greatest improvement in terms of survival during the last decade due to trastuzumab based therapy. Recently, taxane and HER2 directed doublet including trastuzumab and pertuzumab (THP) is considered as standard of therapy based upon randomized phase 3 clinical trial (CLEOTATRA).
Read more
HER2 positive breast cancer can be divided into HER2 enriched subgroup (HR-HER2+) and luminal B subgroup (HR+HER2+) in biologic viewpoint because they are distinctly different subgroups in gene expression analysis. Accordingly, we are currently treating biologically different subtypes in a same way, which is CTx and anti-HER2 combination therapy (THP).
Luminal HER2+ subgroup has actually been tested with endocrine therapy (ET) and anti-HER2 therapy showed better PFS than ET alone (TAnDEM trial and trial comparing lapatinib plus letrozole versus letrozole alone) [2],[3] confirming existence of cross talk between ER and HER2 pathways in clinical setting. However, the combination regimen between ET and anti-HER2 therapy is not widely used in current practice in ER+HER2+ MBC patients because PFS seemed to be relatively shorter compared with chemotherapy based combination with anti-HER2 therapy even though several guidelines recommend it to be used as an initial treatment unless there is visceral crisis as they recommended ET alone first in ER+HER2- MBC (NCCN 2018).
Recently, various CDK4/6 inhibitors including palbociclib, abemaciclib, and ribociclib were approved by FDA based on the clinical trial results demonstrating prolonged PFS over ET alone when it was combined with ET in ER+ advanced breast cancer [4]. In PALOMA 2 biomarker study, it was beneficial regardless of ER and Ki67 expression status.
Reflecting quite durable PFS prolongation (10 month in PALOMA2) shown in ER+ disease (luminal A and luminal B subtype except HR+HER2+ patients) with CDK4/6 inhibitor on top of ET, the hypothesis of this trial is whether CDK4/6 inhibitor could prolong survival in luminal HER2 breast cancer as it did in ER+HER2-patients. In preclinical study, palbociclib showed activity in not only ER+ cell lines but also HER2 positive cell lines [5]. Also, in phase Ib trial, a CDK4/6 inhibitor from Lilly, abemaciclib showed acceptable toxicity with endocrine therapy or trastuzumab with response rate of around 20%.
Hence, as of today, it could be justified and warranted to conduct a prospective trial of ribocicib+letrozole+trastuzumab in order to take a look at its efficacy and toxicity in HR+HER2 + advanced breast cancer.
Read the detailed description
This trial is performed in a multicenter, single-group, and phases IB and II clinical trial.
This is a single-group clinical trial of the effects of ribociclib, letrozole and trastuzumab in postmenopausal women with HR+, HER2+ advanced breast cancer. This trial consists of two parts. The first part is a phase IB study of increasing the dose of ribociclib from 200mg to 600mg in combination with letrozole 2.5mg and trastuzumab (8mg/kg followed by 6mg/kg every 3 weeks). In phase IB study, three to six patients will be enrolled for each dose group.
When the IB phase ends, patient enrollment will be discontinued for intermediate safety analysis, and after DLT analysis will determine recommended phase II phase II part will be started. The recommended phase II dose of ribocicib determined in phase IB part with ribociclib and trastuzumab (8mg/kg followed by 6mg/kg every 3 weeks) will be administered. Treatment is discontinued in the following cases.
- Progression of disease
- Uncontrolled toxicity
- Patient's death
- Withdrawal of consent In phase II part, 61 patients will be enrolled and the first 20 patients will be analyzed for run-in phase to confirm the safety of the therapy.
Regardless of treatment cycle, the disease will be evaluated in the same manner as the method used at the time of registration at intervals of 8 weeks for the first 18 months and at intervals of 12 weeks after that. If the progress of the disease is clinically suspected, additional tests can be performed
- Being tested
- Ribociclib, Trastuzumab, Letrozole
- Keywords
- HR-positive, HER2-positive, Breast Cancer, Hormone-positive, CDK4/6 inhibitor
- 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, Trastuzumab, LetrozoleDrug
Phase IB: letrozole 2.5mg (fixed dose), trastuzumab (8mg/kg loading followed by 6mg/kg q 3weeks, fixed dose) plus ribociclib (dose escalation from 200mg to 600mg) to identify recommended phase iI dose (RPIID) Phase II: letrozole, trastuzumab (same as phase IB) plus ribocicilb RPIID
| Study group | Role | What they receive |
|---|---|---|
| Combination of Letrozole, Trastuzumab with Ribociclib | Experimental | Phase IB (dose escalation of ribociclib with fixed dose of letrozole and Ribociclib) Phase II (ribociclib of RPIID with fixed dose of letrozole and ribociclib) Receives: Drug: Ribociclib, Trastuzumab, Letrozole |
What is being measured
The primary outcome is the main question the study is designed to answer.
Progression free survival
Progression free survival is defined as the time from the start of investigational drug to disease progression or patient's death whichever occurred first
Measured: 1 year
Secondary outcomes (3)
Overall survival
Overall survival is the time from the start of investigational drug to patient's death.
Measured: 1 year
Response rate
Response rate is defined as the response to the drug according to RECIST v1.1 criteria.
Measured: 1 year
Quality of life
Overall survival is the time from the start of investigational drug to patient's death Response rate is defined as the response to the drug according to RECIST v1.1 criteria Quality of life will be measured using EORTC-QLQ C30 questionaire. (Purpose of EORTC-QLQ C30 is to measure the quality of life of the subjects who participated in the clinical study. It consists of 30 questions and each question will be answered by 4 scale answers "Not at all", "A little", "Quite a bit", and "Very much".)
Measured: 1 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Apr 2019
- Study start10 Jun 2019
- Primary completion30 Oct 2023 (estimated)
- Study completion30 Oct 2023 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for HER2-positive Breast CancerStudies of the same condition, open and under way.
- More trials run by Yonsei UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
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 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 95 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Yonsei University
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03913234
- Sponsor's protocol ID
- 4-2018-0765
- Status last verified
- May 2022
- First submitted
- 10 Apr 2019
- Last updated
- 10 May 2022
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 10 May 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase IB & II Study of Ribociclib With Trastuzumab Plus Letrozole in Postmenopausal HR+, HER2+ Advanced Breast Cancer Patients
- ClinicalTrials.gov ID
- NCT03913234
- Acronym / sponsor ID
- 4-2018-0765
- Keywords
- HR-positive, HER2-positive, Breast Cancer, Hormone-positive, CDK4/6 inhibitor
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 95 participants (estimated)
- Lead sponsor
- Yonsei UniversityUniversity, hospital or other
- Study start
- 10 Jun 2019 (actual)
- Primary completion
- 30 Oct 2023 (estimated)
- Study completion
- 30 Oct 2023 (estimated)
- First posted
- 12 Apr 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Survival benefit and quality of life are two key elements that should be kept in mind in the treatment of metastatic breast cancer. In this regards, endocrine therapy (ET) is strongly recommended in hormone receptor (HR) positive patients unless there is visceral crisis even though there is no concrete evidence that it is better than chemotherapy in terms of survival.
HER2 positive breast cancer is a subtype of breast cancer that showed the greatest improvement in terms of survival during the last decade due to trastuzumab based therapy. Recently, taxane and HER2 directed doublet including trastuzumab and pertuzumab (THP) is considered as standard of therapy based upon randomized phase 3 clinical trial (CLEOTATRA).
HER2 positive breast cancer can be divided into HER2 enriched subgroup (HR-HER2+) and luminal B subgroup (HR+HER2+) in biologic viewpoint because they are distinctly different subgroups in gene expression analysis. Accordingly, we are currently treating biologically different subtypes in a same way, which is CTx and anti-HER2 combination therapy (THP).
Luminal HER2+ subgroup has actually been tested with endocrine therapy (ET) and anti-HER2 therapy showed better PFS than ET alone (TAnDEM trial and trial comparing lapatinib plus letrozole versus letrozole alone) [2],[3] confirming existence of cross talk between ER and HER2 pathways in clinical setting. However, the combination regimen between ET and anti-HER2 therapy is not widely used in current practice in ER+HER2+ MBC patients because PFS seemed to be relatively shorter compared with chemotherapy based combination with anti-HER2 therapy even though several guidelines recommend it to be used as an initial treatment unless there is visceral crisis as they recommended ET alone first in ER+HER2- MBC (NCCN 2018).
Recently, various CDK4/6 inhibitors including palbociclib, abemaciclib, and ribociclib were approved by FDA based on the clinical trial results demonstrating prolonged PFS over ET alone when it was combined with ET in ER+ advanced breast cancer [4]. In PALOMA 2 biomarker study, it was beneficial regardless of ER and Ki67 expression status.
Reflecting quite durable PFS prolongation (10 month in PALOMA2) shown in ER+ disease (luminal A and luminal B subtype except HR+HER2+ patients) with CDK4/6 inhibitor on top of ET, the hypothesis of this trial is whether CDK4/6 inhibitor could prolong survival in luminal HER2 breast cancer as it did in ER+HER2-patients. In preclinical study, palbociclib showed activity in not only ER+ cell lines but also HER2 positive cell lines [5]. Also, in phase Ib trial, a CDK4/6 inhibitor from Lilly, abemaciclib showed acceptable toxicity with endocrine therapy or trastuzumab with response rate of around 20%.
Hence, as of today, it could be justified and warranted to conduct a prospective trial of ribocicib+letrozole+trastuzumab in order to take a look at its efficacy and toxicity in HR+HER2 + advanced breast cancer.
Detailed description
This trial is performed in a multicenter, single-group, and phases IB and II clinical trial.
This is a single-group clinical trial of the effects of ribociclib, letrozole and trastuzumab in postmenopausal women with HR+, HER2+ advanced breast cancer. This trial consists of two parts. The first part is a phase IB study of increasing the dose of ribociclib from 200mg to 600mg in combination with letrozole 2.5mg and trastuzumab (8mg/kg followed by 6mg/kg every 3 weeks). In phase IB study, three to six patients will be enrolled for each dose group.
When the IB phase ends, patient enrollment will be discontinued for intermediate safety analysis, and after DLT analysis will determine recommended phase II phase II part will be started. The recommended phase II dose of ribocicib determined in phase IB part with ribociclib and trastuzumab (8mg/kg followed by 6mg/kg every 3 weeks) will be administered. Treatment is discontinued in the following cases.
- Progression of disease
- Uncontrolled toxicity
- Patient's death
- Withdrawal of consent In phase II part, 61 patients will be enrolled and the first 20 patients will be analyzed for run-in phase to confirm the safety of the therapy.
Regardless of treatment cycle, the disease will be evaluated in the same manner as the method used at the time of registration at intervals of 8 weeks for the first 18 months and at intervals of 12 weeks after that. If the progress of the disease is clinically suspected, additional tests can be performed
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Combination of Letrozole, Trastuzumab with Ribociclib | Experimental | Drug: Ribociclib, Trastuzumab, LetrozolePhase IB (dose escalation of ribociclib with fixed dose of letrozole and Ribociclib) Phase II (ribociclib of RPIID with fixed dose of letrozole and ribociclib) |
Who may qualify
- Ages
- 19 years and older
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (21 listed)
- Patients aged ≥19 years
- Women with advanced (loco-regionally recurrent or metastatic) breast cancer not amenable for curative therapy
- Histologically and/or cytologically confirmed estrogen receptor positive and/or progesterone receptor positive breast cancer
- HER2 positive breast cancer (IHC 3+ or IHC 2+ and FISH, SISH or CISH+)
- Postmenopausal patient defined as either one of the following.
Key exclusion criteria (13 listed)
- Patients who have previously received CDK4 / 6 inhibitors or who have received other systemic treatments for advanced / metastatic breast cancer (Previous neo-adjuvant of adjuvant trastuzumab or aromatase inhibitor is not allowed, unless
- Disease free interval was more than 12 months from the last dose of adjuvant trastuzumab or
- Adjuvant aromatase inhibitor was administered more than 2 years)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Ribociclib, Trastuzumab, LetrozolePhase IB: letrozole 2.5mg (fixed dose), trastuzumab (8mg/kg loading followed by 6mg/kg q 3weeks, fixed dose) plus ribociclib (dose escalation from 200mg to 600mg) to identify recommended phase iI dose (RPIID) Phase II: letrozole, trastuzumab (same as phase IB) plus ribocicilb RPIID | Drug | Combination of Letrozole, Trastuzumab with Ribociclib |
Primary outcome
Progression free survival
Time frame: 1 year
Progression free survival is defined as the time from the start of investigational drug to disease progression or patient's death whichever occurred first
3 secondary outcomes
Overall survival
Time frame: 1 year
Response rate
Time frame: 1 year
Quality of life
Time frame: 1 year
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 May 2022.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Ribociclib, Trastuzumab, Letrozole in people with HER2-positive Breast Cancer and Postmenopausal, run by Yonsei University at 1 site in South Korea.
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 21 inclusion and 13 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: status not confirmed, as of the sponsor's last update on 10 May 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in South Korea. 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 combined 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.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Joo Hyuk Sohn, Md, PhD (82-2-2228-8135, oncosohn@yuhs.ac), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Progression free survival (time frame: 1 year). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 10 May 2022.