PRECIOUS: A Phase III Trial of Pertuzumab Retreatment in Previously Pertuzumab Treated Her2-Positive Advanced Breast Cancer
Study Details
Study Description
Brief Summary
The purpose of this study is to evaluate the efficacy and safety of pertuzumab, trastuzumab and chemotherapy as a pertuzumab retreatment compared to trastuzumab and chemotherapy in locally advanced or metastatic breast cancer patients for previously treated with pertuzumab
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 3 |
Detailed Description
The American Society of Clinical Oncology (ASCO) Clinical Practice Guidelines recommend the use of pertuzumab, trastuzumab and taxane as first-line treatment for patients with MBC. As a second-line treatment, trastuzumab emtansine (T-DM1) is also recommended. After a pertuzumab-containing regimen and T-DM1, other HER2-targeted therapeutic regimens, including lapatinib-containing regimens and trastuzumab plus chemotherapy, are recommended as third-line treatments and beyond. However, continual pertuzumab use for progression after a pertuzumab-containing regimen and retreatment with pertuzumab are unclear based on evidence.
The efficacy and the safety of two distinct modalities of a trastuzumab plus pertuzumab-containing regimen after pertuzumab use should be assessed in MBC: continual treatment and retreatment. However, it is clinically difficult to examine the efficacy of continual treatment with a trastuzumab plus pertuzumab-containing regimen because of several circumstances including the results of the MARIANNE study.
In addition, it is also important to evaluate the usefulness of retreatment with a pertuzumab-containing regimen. Continual pertuzumab treatment for progression after pertuzumab treatment is not same as pertuzumab retreatment. HER2-HER3-signaling suppressed by pertuzumab-containing regimens could potentially be restored by anti-HER2 therapy without pertuzumab. Pertuzumab retreatment could potentially re-suppress HER2-HER3-signaling. Therefore, Pertuzumab retreatment can be more effective than trastuzumab-containing treatment without pertuzumab.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: Trastuzumab + chemotherapy Trastuzumab + chemotherapy Chemotherapy regimen is chosen from the following; Docetaxel, Paclitaxel, nab-paclitaxel ,Vinorelbine, Eribulin, Capecitabine or Gemcitabine |
Drug: Trastuzumab
Other Names:
Drug: Docetaxel
Other Names:
Drug: Paclitaxel
Other Names:
Drug: Nab-paclitaxel
Other Names:
Drug: Vinorelbine
Other Names:
Drug: Eribulin
Other Names:
Drug: Capecitabine
Other Names:
Drug: Gemcitabine
Other Names:
|
| Experimental: Trastuzumab+ pertuzumab + chemotherapy Trastuzumab+ pertuzumab + chemotherapy Chemotherapy regimen is chosen from the following; Docetaxel, Paclitaxel, nab-paclitaxel, Vinorelbine, Eribulin, Capecitabine or Gemcitabine |
Drug: Trastuzumab
Other Names:
Drug: Pertuzumab
Other Names:
Drug: Docetaxel
Other Names:
Drug: Paclitaxel
Other Names:
Drug: Nab-paclitaxel
Other Names:
Drug: Vinorelbine
Other Names:
Drug: Eribulin
Other Names:
Drug: Capecitabine
Other Names:
Drug: Gemcitabine
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Progression-free survival (assessed by investigators) [4 years]
Secondary Outcome Measures
- Progression-free survival (assessed by independent review) [4 years]
- PFS in patients treated with trastuzumab emtansine (T-DM1) as the latest regimen [4 years]
- Response rate [4 years]
- Duration of response, Overall survival [4 years]
- Patient-reported-outcome [4 years]
Difference in terms of patient-reported outcome (PRO) between standard group and Pertuzumab treated group FACT-G, FACT-B and EQ-5D are used as assessment tools for PRO.
- Safety assessed by Incidence/Grade of Serious Adverse Events (SAEs), Pertuzumab-specific adverse events, laboratory abnormalities Percentage and number of subjects who discontinued for adverse event. [4 years]
Safety for HER2-positive locally advanced or metastatic breast cancer subjects who were previously treated with Pertuzumab
- Biomarkers [4 years]
To find Prognostic and predictive biomarker markers for patients receiving anti-HER2 treatment. Changes in immunologic markers on peripheral blood mononuclear cells determined by flow cytometry after anti-HER2 treatment Changes in tumor-derived gene mutations (e.g. PIK3CA, APOBEC3, CDH1…etc.) in ctDNA after anti-HER2 therapy Changes in proteins (e.g. HER2, HER3…etc.) and micro RNAs expression in extracellular vesicle after anti-HER2 therapy Changes in glycans and proteins expression in the plasma after anti-HER2 therapy.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Histologically or cytologically confirmed invasive breast cancer
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A confirmed HER2-positive status assessed by means of immunohistochemical analysis (with 3+ indicating positive status) and/or in situ hybridization (with an amplification ratio > 2.0 indicating positive) by each institute
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History of pertuzumab and trastuzumab-containing chemotherapy for locally advanced and metastatic breast cancer(2 or 3 regimen as previous chemotherapy regimen for locally advanced or metastatic breast cancer). The latest regimen before enrollment dose not include pertuzumab.
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Patients have measurable and/or non-measurable disease according to RECIST ver1.1.
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Female patients and aged ≥ 20 years.
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Left Ventricular Ejection Fraction (LVEF) > 50% at baseline (within 28 days before enrollment) as determined by either ECHO or MUGA
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Eastern Cooperative Oncology Group performance status of 0,1 or 2.
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Life expectancy of patients is expected at least 3 months.
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Signed and written informed consent (approved by the Institutional Review Board or Independent Ethics Committee) is obtained before any study procedure.
Exclusion Criteria:
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History of chemotherapy > 4 regimen for locally advance or metastatic disease except for cancer chemotherapeutic agent-free treatment regimen (eg, hormonal therapy alone, combination with hormonal therapy and trastuzumab and anti-HER2 therapy alone).
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Persistent Grade >3 non-hematologic toxicity according to NCI-CTCAE v4.0-JCOG resulting from previous therapy at the time of enrollment.
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Symptomatic or uncontrolled central nervous system metastases.
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Multiple malignancies without history of breast cancer(within 10 years if invasive breast cancer and within 5 years if malignancies except invasive breast cancer)
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History of exposure to the following cumulative doses of anthracyclines:
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doxorubicin or liposomal doxorubicin > 360 mg/m2
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epirubicin > 720 mg/m2
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mitoxantrone > 100 mg/m2
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If more than 1 anthracycline has been used, then the cumulative dose must not exceed the equivalent of 360 mg/m2 of doxorubicin.
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Current uncontrolled hypertension (systolic > 150 mmHg and/or diastolic > 100 mmHg) or unstable angina.
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History of CHF of any New York Heart Association criteria, or serious cardiac arrhythmia requiring treatment (exception, atrial fibrillation, paroxysmal supraventricular tachycardia).
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History of myocardial infarction within 6 months of enrollment.
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Dyspnea at rest due to complications of advanced malignancy.
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Inadequate organ function, as determined by the following laboratory results, within 28 days before enrollment:
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Absolute neutrophil count < 1,500/mm3
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Platelet count < 100,000/mm3
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Hemoglobin < 8.0 g/dL
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Total bilirubin > 2.0 mg/dL, unless the patient has documented Gilbert's syndrome
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Aspartate aminotransferase (AST [SGOT]) or alanine aminotransferase (ALT [SGPT])
100IU /L with the following exception (If considered that the liver dysfunction due to liver metastases > 200 IU/L, or 100 < , ≤200 IU/L with serum albumin < 2.5 g/dL)
- Serum creatinine value > 2.0 mg/dL or 177 μmol/L
- Current severe uncontrolled systemic disease(eg. Clinically significant cardiovascular, pulmonary and metabolic disease*, disorder of wound healing, ulcer and fracture)
*If gemcitabine is planned to be selected as a combination chemotherapeutic agent,patients who has symptomatic interstitial pneumonia or pulmonary fibrosis on chest X-ray should be excluded.
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Uncontrolled malignancy-associated hypercalcemia syndrome under bisphosphonates or denosumab treatment.
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Radiation related grade >2 adverse event within 14 days before enrollment.
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Major surgical procedure or significant traumatic injury within 28 days before enrollment or anticipation of need for major surgery during the course of study treatment.
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Pregnant woman or positive pregnancy test.
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Nursing woman
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History of receiving any investigational treatment within 28 days before enrollment.
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Current known and active infection with human immunodeficiency virus, hepatitis B virus or hepatitis C virus.
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Receipt of intravenous antibiotics for infection within 14 days before enrollment.
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Current chronic daily treatment (continuous for > 3 months) with corticosteroids (dose equivalent to or greater than 10 mg/day methylprednisolone), excluding inhaled steroids.
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Known hypersensitivity to pertuzumab or trastuzumab without infusion reaction related to these drugs
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Assessed by the investigator to be unable or unwilling to comply with the requirements of the protocol.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Aichi Cancer Center | Chikusa-ku | Aichi | Japan | 4648681 |
| 2 | Kumamoto University Hospital | Kumamoto City | Kumamoto | Japan | 8608556 |
| 3 | Japan Breast Cancer Research Group | Chuo-ku, Nihonbashi, Koami-cho | Tokyo | Japan | 1030016 |
Sponsors and Collaborators
- Japan Breast Cancer Research Group
- Chugai Pharmaceutical
Investigators
- Principal Investigator: Hiroji Iwata, MD, PhD, Aichi Cancer Center Hospital
- Principal Investigator: Yutaka Yamamoto, MD, PhD, Kumamoto University Hospital
Study Documents (Full-Text)
None provided.More Information
Publications
- Baselga J, Cortés J, Kim SB, Im SA, Hegg R, Im YH, Roman L, Pedrini JL, Pienkowski T, Knott A, Clark E, Benyunes MC, Ross G, Swain SM; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012 Jan 12;366(2):109-19. doi: 10.1056/NEJMoa1113216. Epub 2011 Dec 7.
- Giordano SH, Temin S, Kirshner JJ, Chandarlapaty S, Crews JR, Davidson NE, Esteva FJ, Gonzalez-Angulo AM, Krop I, Levinson J, Lin NU, Modi S, Patt DA, Perez EA, Perlmutter J, Ramakrishna N, Winer EP; American Society of Clinical Oncology. Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2014 Jul 1;32(19):2078-99. doi: 10.1200/JCO.2013.54.0948. Epub 2014 May 5. Review.
- Lee-Hoeflich ST, Crocker L, Yao E, Pham T, Munroe X, Hoeflich KP, Sliwkowski MX, Stern HM. A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy. Cancer Res. 2008 Jul 15;68(14):5878-87. doi: 10.1158/0008-5472.CAN-08-0380.
- Perez EA, Barrios C, Eiermann W, Toi M, Im YH, Conte P, Martin M, Pienkowski T, Pivot X, Burris H 3rd, Petersen JA, Stanzel S, Strasak A, Patre M, Ellis P. Trastuzumab Emtansine With or Without Pertuzumab Versus Trastuzumab Plus Taxane for Human Epidermal Growth Factor Receptor 2-Positive, Advanced Breast Cancer: Primary Results From the Phase III MARIANNE Study. J Clin Oncol. 2017 Jan 10;35(2):141-148. Epub 2016 Nov 7. Erratum in: J Clin Oncol. 2017 Jul 10;35(20):2342. J Clin Oncol. 2019 Feb 1;37(4):358.
- JBCRG-M05