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

Fudan University

Status and phase: Enrolling; Phase 2

Conditions: Metastatic Cancer; Breast Cancer

Treatments: Drug: Famitinib; Drug: SHR1210; Drug: Nab paclitaxel; Drug: SHR1701; Drug: Capecitabine; Drug: Pyrotinib; Drug: Everolimus; Drug: SHR6390; Drug: SHR7390; Drug: VEGFi; Drug: SHR2554; Drug: SHR3680; Drug: SERD; Drug: SHR3162; Drug: AI

Study type: Interventional

Funder types: Other

Identifiers

NCT04355858

SCHBCC-N029

Details and patient eligibility

About

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.

Full 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.

Enrollment: 319 estimated patients

Sex: Female

Ages: 18 to 75 years old

Volunteers: No 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).

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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319 participants in 9 patient groups

NF1 mutated

Experimental group

Description:

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

Treatment:

Drug: Famitinib

Drug: SHR7390

gBRCA mutated

Experimental group

Description:

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

Treatment:

Drug: SHR3162

Drug: SHR6390

HER2 activated mutated

Experimental group

Description:

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.

Treatment:

Drug: Pyrotinib

Drug: Capecitabine

PDGFRb mutated

Experimental group

Description:

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

Treatment:

Drug: Famitinib

CD8 ≥10%

Experimental group

Description:

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.

Treatment:

Drug: AI

Drug: VEGFi

Drug: SHR1210

Drug: Nab paclitaxel

Drug: Famitinib

Drug: SHR1701

Drug: SERD

Drug: SHR6390

PAM pathway mutated

Experimental group

Description:

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

Treatment:

Drug: Everolimus

Drug: Nab paclitaxel

AR≥10%

Experimental group

Description:

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

Treatment:

Drug: SHR2554

Drug: SHR3680

Epigenetic Cohort

Experimental group

Description:

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

Treatment:

Drug: SHR2554

Drug: SHR3162

Combined Immunity Cohort

Experimental group

Description:

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

Treatment:

Drug: SHR1701

Drug: SHR6390