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Molecularly Targeted Umbrella Study in Luminal Advanced Breast Cancer (MULAN)

Primary Purpose

Breast Cancer, Metastatic Cancer

Status

Recruiting

Phase

Phase 2

Locations

China

Study Type

Interventional

Intervention

SHR7390

Famitinib

SHR3162

Pyrotinib

Capecitabine

SHR1210

Everolimus

Nab paclitaxel

SHR2554

SHR3680

SHR6390

SHR1701

SERD

VEGFi

About this trial

This is an interventional treatment trial for Breast Cancer focused on measuring first-line therapy

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)FemaleDoes not accept healthy volunteers

Inclusion Criteria:

Females ≥18 years old;
Histologically confirmed HR + / HER2- invasive breast cancer (specific definition: immunohistochemical detection of ER> 10% tumor cell positive is defined as ER positive, PR> 10% tumor cell positive is defined as PR positive, ER and / or PR Positive is defined as HR positive; HER2 0-1 + or HER2 is ++ but negative followed by FISH detection, no amplification, defined as HER2 negative);
Locally advanced breast cancer (incapable of radical local treatment) or recurrent metastatic breast cancer;
Patients with HR+/HER2- advanced breast cancer who were previously treated with CDK4 / 6 inhibitor except for Arm 5E-5F;
Measurable disease according to Response Evaluation Criteria in Solid Tumors v1.1 (RECIST v1.1)
Has adequate bone marrow function: absolute neutrophil count > 1.5x10ˆ9 /L; platelet count > 75x10ˆ9 /L, hemoglobin > 9g/dL;
Has adequate liver function: alanine aminotransferase (ALT) ≤1.5×upper limit of normal (ULN), aspartate aminotransferase (AST) ≤3×ULN, alkaline phosphatase (AKP) ≤3×ULN, total bilirubin (TBIL) ≤ 1.5×ULN.
Has adequate kidney function: serum creatinine ≤1×ULN.Endogenous creatinine clearance> 50 ml / min (Cockcroft-Gault formula);
Did not receive radiation, molecular targeted therapy or surgery within 3 weeks before the study began, and has recovered from the acute toxicity of previous treatment (if surgery, the wound has completely healed); no peripheral neuropathy or first degree peripheral neurotoxicity ;
ECOG score ≤ 2 and life expectancy ≥ 3 months;
Participants voluntarily joined the study, has signed informed consent before any trial related activities are conducted, has good compliance and has agreed to follow-up.

Exclusion Criteria:

Treatment with chemotherapy, radiotherapy, immunotherapy or surgery (outpatient clinic surgery excluded)within3 weeks prior to initiation of study treatment(bisphosphonates can be used for bone metastasis);
Symptomatic, untreated, or actively progressing CNS metastases(glucocorticoids or mannitol needed to control symptoms);
Significant cardiovascular disease(including congestive heart failure, angina pectoris, myocardial infarction or ventricular arrhythmia in the last 6 months);
Grade ≥ 1 adverse reactions that are ongoing due to previous treatment. Exceptions to this are hair loss or the investigator's opinion should not be ruled out. Such cases should be clearly documented in the investigator's notes;
Is pregnant or breast feeding;
Malignant tumors in the past five years (except cured skin basal cell carcinoma and cervical carcinoma in situ).

Sites / Locations

Cancer Hospital Affiliated to Fudan UniversityRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm 8

Arm 9

Arm Type

Experimental

Arm Label

NF1 mutated

gBRCA mutated

HER2 activated mutated

PDGFRb mutated

CD8 ≥10%

PAM pathway mutated

AR≥10%

Epigenetic Cohort

Combined Immunity Cohort

Arm Description

If a patient were NF1 mutated, she would receive SHR7390(MEK1/2 inhibitor) and Faminitib.

If a patient were gBRCA mutated, she would receive SHR3162 (PARP inhibitor)and SHR6390(CDK4/6 inhibitor) .

If a patient were HER2 activated mutated and had not previously used capecitabine, she would receive Pyrotinib and Capecitabine , while if the patient have previously used capecitabine, she would only use pyrotinib as a single agent.

If a patient were PDGFRb mutated, she would receive Faminitib.

In the arm which IHC showed CD8 ≥10%, this arm will be subdivided into 6 sub-arms, in which Arm 5A-4D, we choose the patients who had CDK4/6 inhibitor before while in Arm 5E, we choose the patients who secondarily resistant to adjuvant endocrine therapy , and in Arm 5FF, we choose the patients who is in stage IV without precious treatment or sensitively recurrence. A patient would receive SHR1210(PD-1 antibody) ,nab-paclitaxel and Faminitib in Arm-5A. A patient would receive SHR1210(PD-1 antibody) and VEGF inhibitor in Arm-5B. A patient would receive SHR1701(PD-L1/TGF-βRII inhibitor) in Arm-5C. A patient would receive SHR1701(PD-L1/TGF-βRII inhibitor) and SHR6390(CDK4/6 inhibitor) in Arm-5D. A patient would receive SHR1210(PD-1 antibody) and SHR6390(CDK4/6 inhibitor) and SERD in Arm-5E. A patient would receive SHR1210(PD-1 antibody) and SHR6390(CDK4/6 inhibitor) and AI in Arm-5F.

If a patient had any PAM pathway mutation, she would receive Everolimus(mTOR inhibitor) combined with nab-paclitaxel.

If a patient's IHC showed AR≥10% , she would receive SHR2554(EZH2 inhibitor) and SHR3680(AR inhibitor).

In this cohort, a patient would receive SHR2554(EZH2 inhibitor) and SHR3162 (PARP inhibitor).

In this cohort, a patient would receive SHR6390(CDK4/6 inhibitor) combined with SHR1701(anti-PD-L1/TGF-βRII bifunctional fusion protein) .

Outcomes

Primary Outcome Measures

ORR

The proportion of participants whose best outcome is complete remission or partial remission (according to RECIST1.1)

Secondary Outcome Measures

CBR

the percentage of subjects with CR+PR+SD and last more than 24 weeks in all of the evaluable subjects

PFS

time to progressive disease (according to RECIST1.1)

time to death due to any cause

Full Information

NCT ID

NCT04355858

First Posted

April 17, 2020

Last Updated

July 22, 2022

Sponsor

Fudan University

1. Study Identification

Unique Protocol Identification Number

NCT04355858

Brief Title

Molecularly Targeted Umbrella Study in Luminal Advanced Breast Cancer

Acronym

MULAN

Official Title

Precision Treatment of Luminal Advanced Breast Cancer Based on Molecular Subtyping

Study Type

Interventional

2. Study Status

Record Verification Date

July 2022

Overall Recruitment Status

Recruiting

Study Start Date

May 1, 2020 (Actual)

Primary Completion Date

May 1, 2023 (Anticipated)

Study Completion Date

April 1, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Fudan University

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

This study is a prospective, single-center, open-label, umbrella-shaped phase II clinical study for patients with HR+/HER2- endocrine-resistant advanced breast cancer.

Detailed Description

Seven precision treatment cohorts, which targeting NF1 mutation, gBRCA mutation,HER2 mutation, FDGFRb mutation PAM pathway mutations, CD8 and AR, as long as an epigenetic therapy cohort and a combined immunization cohort were initially set up based on gene expression profiles and molecular pathways. The main purpose is to screen valuable treatment cohorts and prepare for subsequent randomized controlled phase III clinical studies with larger sample size.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Breast Cancer, Metastatic Cancer

Keywords

first-line therapy

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

319 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

NF1 mutated

Arm Type

Experimental

Arm Description

If a patient were NF1 mutated, she would receive SHR7390(MEK1/2 inhibitor) and Faminitib.

Arm Title

gBRCA mutated

Arm Type

Experimental

Arm Description

If a patient were gBRCA mutated, she would receive SHR3162 (PARP inhibitor)and SHR6390(CDK4/6 inhibitor) .

Arm Title

HER2 activated mutated

Arm Type

Experimental

Arm Description

Arm Title

PDGFRb mutated

Arm Type

Experimental

Arm Description

If a patient were PDGFRb mutated, she would receive Faminitib.

Arm Title

CD8 ≥10%

Arm Type

Experimental

Arm Description

Arm Title

PAM pathway mutated

Arm Type

Experimental

Arm Description

If a patient had any PAM pathway mutation, she would receive Everolimus(mTOR inhibitor) combined with nab-paclitaxel.

Arm Title

AR≥10%

Arm Type

Experimental

Arm Description

If a patient's IHC showed AR≥10% , she would receive SHR2554(EZH2 inhibitor) and SHR3680(AR inhibitor).

Arm Title

Epigenetic Cohort

Arm Type

Experimental

Arm Description

In this cohort, a patient would receive SHR2554(EZH2 inhibitor) and SHR3162 (PARP inhibitor).

Arm Title

Combined Immunity Cohort

Arm Type

Experimental

Arm Description

In this cohort, a patient would receive SHR6390(CDK4/6 inhibitor) combined with SHR1701(anti-PD-L1/TGF-βRII bifunctional fusion protein) .

Intervention Type

Drug

Intervention Name(s)

SHR7390

Intervention Description

MEK1/2 inhibitor

Intervention Type

Drug

Intervention Name(s)

Famitinib

Intervention Description

Multi-target tyrosine kinase inhibitor

Intervention Type

Drug

Intervention Name(s)

SHR3162

Intervention Description

PARP inhibitor

Intervention Type

Drug

Intervention Name(s)

Pyrotinib

Intervention Description

HER1 / HER2 receptor tyrosine kinase inhibitor

Intervention Type

Drug

Intervention Name(s)

Capecitabine

Intervention Description

In Arm III, if the patient had not previously used capecitabine,she would receive pyrotinib and capecitabine, if the patients have previously used capecitabine, she would only used pyrotinib as a single agent.

Intervention Type

Drug

Intervention Name(s)

SHR1210

Intervention Description

PD-1 antibody

Intervention Type

Drug

Intervention Name(s)

Everolimus

Intervention Description

mTOR inhibitor

Intervention Type

Drug

Intervention Name(s)

Nab paclitaxel

Intervention Description

Albumin bound paclitaxel

Intervention Type

Drug

Intervention Name(s)

SHR2554

Intervention Description

EZH2 inhibitor

Intervention Type

Drug

Intervention Name(s)

SHR3680

Intervention Description

AR inhibitor

Intervention Type

Drug

Intervention Name(s)

SHR6390

Intervention Description

CDK4/6 inhibitor

Intervention Type

Drug

Intervention Name(s)

SHR1701

Intervention Description

anti-PD-L1/TGF-βRII bifunctional fusion protein

Intervention Type

Drug

Intervention Name(s)

SERD

Intervention Description

Fulvestrant

Intervention Type

Drug

Intervention Name(s)

Intervention Description

aromatase inhibitor

Intervention Type

Drug

Intervention Name(s)

VEGFi

Intervention Description

Bevacizumab

Primary Outcome Measure Information:

Title

ORR

Description

The proportion of participants whose best outcome is complete remission or partial remission (according to RECIST1.1)

Time Frame

Randomization until the first occurrence of disease progression or death from any cause, which ever occurs first, through the end of study (approximately 5 years)

Secondary Outcome Measure Information:

Title

CBR

Description

the percentage of subjects with CR+PR+SD and last more than 24 weeks in all of the evaluable subjects

Time Frame

Randomization until the first occurrence of disease progression or death from any cause, which ever occurs first, through the end of study (approximately 5 years)

Title

PFS

Description

time to progressive disease (according to RECIST1.1)

Time Frame

Randomization until the first occurrence of disease progression or death from any cause, which ever occurs first, through the end of study (approximately 5 years)

Title

Description

time to death due to any cause

Time Frame

Randomization to death from any cause, through the end of study (approximately 5 years)

10. Eligibility

Sex

Female

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Females ≥18 years old; Histologically confirmed HR + / HER2- invasive breast cancer (specific definition: immunohistochemical detection of ER> 10% tumor cell positive is defined as ER positive, PR> 10% tumor cell positive is defined as PR positive, ER and / or PR Positive is defined as HR positive; HER2 0-1 + or HER2 is ++ but negative followed by FISH detection, no amplification, defined as HER2 negative); Locally advanced breast cancer (incapable of radical local treatment) or recurrent metastatic breast cancer; Patients with HR+/HER2- advanced breast cancer who were previously treated with CDK4 / 6 inhibitor except for Arm 5E-5F; Measurable disease according to Response Evaluation Criteria in Solid Tumors v1.1 (RECIST v1.1) Has adequate bone marrow function: absolute neutrophil count > 1.5x10ˆ9 /L; platelet count > 75x10ˆ9 /L, hemoglobin > 9g/dL; Has adequate liver function: alanine aminotransferase (ALT) ≤1.5×upper limit of normal (ULN), aspartate aminotransferase (AST) ≤3×ULN, alkaline phosphatase (AKP) ≤3×ULN, total bilirubin (TBIL) ≤ 1.5×ULN. Has adequate kidney function: serum creatinine ≤1×ULN.Endogenous creatinine clearance> 50 ml / min (Cockcroft-Gault formula); Did not receive radiation, molecular targeted therapy or surgery within 3 weeks before the study began, and has recovered from the acute toxicity of previous treatment (if surgery, the wound has completely healed); no peripheral neuropathy or first degree peripheral neurotoxicity ; ECOG score ≤ 2 and life expectancy ≥ 3 months; Participants voluntarily joined the study, has signed informed consent before any trial related activities are conducted, has good compliance and has agreed to follow-up. Exclusion Criteria: Treatment with chemotherapy, radiotherapy, immunotherapy or surgery (outpatient clinic surgery excluded)within3 weeks prior to initiation of study treatment(bisphosphonates can be used for bone metastasis); Symptomatic, untreated, or actively progressing CNS metastases(glucocorticoids or mannitol needed to control symptoms); Significant cardiovascular disease(including congestive heart failure, angina pectoris, myocardial infarction or ventricular arrhythmia in the last 6 months); Grade ≥ 1 adverse reactions that are ongoing due to previous treatment. Exceptions to this are hair loss or the investigator's opinion should not be ruled out. Such cases should be clearly documented in the investigator's notes; Is pregnant or breast feeding; Malignant tumors in the past five years (except cured skin basal cell carcinoma and cervical carcinoma in situ).

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Zhi-Ming Shao

Phone

86-021-64175590

Ext

8888

zhimingshao@yahoo.com

First Name & Middle Initial & Last Name or Official Title & Degree

Zhong-Hua Wang

Phone

+86 021-64175590

zhonghuawang95@hotmail.com

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Zhi-Ming Shao

Organizational Affiliation

Fudan University

Official's Role

Principal Investigator

Facility Information:

Facility Name

Cancer Hospital Affiliated to Fudan University

City

Shanghai

State/Province

Shanghai

ZIP/Postal Code

200032

Country

China

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Zhimin Shao, MD, PhD

Phone

+86-021-64175590

Ext

8888

zhimingshao@yahoo.com

12. IPD Sharing Statement

Citations:

PubMed Identifier

33570247

Citation

Chen MK. Efficacy of PARP inhibition combined with EZH2 inhibition depends on BRCA mutation status and microenvironment in breast cancer. FEBS J. 2021 May;288(9):2884-2887. doi: 10.1111/febs.15730. Epub 2021 Feb 11.

Results Reference

derived

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Molecularly Targeted Umbrella Study in Luminal Advanced Breast Cancer

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