High Dose Chemotherapy in Oligo-metastatic Homologous Recombination Deficient Breast Cancer

Sponsor

The Netherlands Cancer Institute (Other)

Overall Status

Recruiting

CT.gov ID

NCT01646034

Collaborator

(none)

Enrollment

Location

Arms

145

Duration (Months)

0.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study investigates the effect of high-dose alkylating chemotherapy compared with standard chemotherapy as part of a multimodality treatment approach in patients with oligo-metastatic breast cancer harboring homologous recombination deficiency.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: carboplatin, thiotepa, and cyclophosphamide Drug: chemotherapy (docetaxel, doxorubicin, cyclofosfamide, carboplatin, paclitaxel, gemcitabine)	Phase 3

Study Design

Study Type:

Interventional

Anticipated Enrollment :

74 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

High-dose Alkylating Chemotherapy in Oligo-metastatic Breast Cancer Harboring Homologous Recombination Deficiency

Study Start Date :

Sep 1, 2014

Anticipated Primary Completion Date :

Jan 1, 2023

Anticipated Study Completion Date :

Oct 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: intensified alkylating chemotherapy a course chemotherapy with high dose cyclophosphamide, G-CSF and peripheral blood progenitor cell (PBPC) harvest followed by tandem intermediate-dose alkylating therapy (miniCTC, carboplatin 800 mg/m2, thiotepa 240 mg/m2, and cyclophosphamide 3000 mg/m2) with PBPC-reinfusion.	Drug: carboplatin, thiotepa, and cyclophosphamide tandem intermediate-dose alkylating therapy: carboplatin 800 mg/m2, thiotepa 240 mg/m2, and cyclophosphamide 3000 mg/m2) with PBPC-reinfusion.
Active Comparator: three cycles of chemotherapy three cycles of chemotherapy depending on previously received agents chemotherapy naïve;three cycles of docetaxel, doxorubicin, and cyclophosphamide previously received anthracyclines without taxanes;three cycles of carboplatin and paclitaxel previously received anthracyclines and taxanes;three cycles of carboplatin and gemcitabine	Drug: chemotherapy (docetaxel, doxorubicin, cyclofosfamide, carboplatin, paclitaxel, gemcitabine) chemotherapy naïve;three cycles of docetaxel, doxorubicin, and cyclofosfamide chemotherapy naïve;1 cycle of dose-dense Adriamycin and cyclophosphamide followed by 4 cycles of carboplatin and paclitaxel previously received anthracyclines without taxanes;three cycles of carboplatin and paclitaxel previously received anthracyclines and taxanes;three cycles of carboplatin and gemcitabine

Arm

Intervention/Treatment

Experimental: intensified alkylating chemotherapy

a course chemotherapy with high dose cyclophosphamide, G-CSF and peripheral blood progenitor cell (PBPC) harvest followed by tandem intermediate-dose alkylating therapy (miniCTC, carboplatin 800 mg/m2, thiotepa 240 mg/m2, and cyclophosphamide 3000 mg/m2) with PBPC-reinfusion.

Drug: carboplatin, thiotepa, and cyclophosphamide

tandem intermediate-dose alkylating therapy: carboplatin 800 mg/m2, thiotepa 240 mg/m2, and cyclophosphamide 3000 mg/m2) with PBPC-reinfusion.

Active Comparator: three cycles of chemotherapy

three cycles of chemotherapy depending on previously received agents chemotherapy naïve;three cycles of docetaxel, doxorubicin, and cyclophosphamide previously received anthracyclines without taxanes;three cycles of carboplatin and paclitaxel previously received anthracyclines and taxanes;three cycles of carboplatin and gemcitabine

Drug: chemotherapy (docetaxel, doxorubicin, cyclofosfamide, carboplatin, paclitaxel, gemcitabine)

chemotherapy naïve;three cycles of docetaxel, doxorubicin, and cyclofosfamide chemotherapy naïve;1 cycle of dose-dense Adriamycin and cyclophosphamide followed by 4 cycles of carboplatin and paclitaxel previously received anthracyclines without taxanes;three cycles of carboplatin and paclitaxel previously received anthracyclines and taxanes;three cycles of carboplatin and gemcitabine

Outcome Measures

Primary Outcome Measures

Event free survival [assessed up to 120 months]
time from randomization to local recurrence, second primary, distant recurrence or death, whichever comes first

Secondary Outcome Measures

Difference in median overall survival [assessed up to 120 months]
time from randomization to death from any cause
Difference in percentage of patients with grade >2 hematologic toxicity (CTCAE v4.0) [6 months after start of treament]
Difference in percentage of patients with grade >2 hematologic toxicity (CTCAE v4.0)
Difference in percentage of patients with grade >2 non-hematologic toxicity (CTCAE v4.0) [6 months after start of treatment]
Difference in percentage of patients with grade >2 non-hematologic toxicity (CTCAE v4.0)
Difference in quality of life (EORTC QLQ-C30 v 3.0) [6 and 12 months post treatment]
Difference in quality of life (EORTC QLQ-C30 v 3.0)
Difference in event free survival [assessed up to 120 months]
o Difference in event free survival in the subgroups based on: Estrogen receptor status; Origin of the oligo-metastatic lesion (lymphnodes versus bone versus visceral metastases); Primary or recurrent oligometastatic breast cancer; BRCA1 mutation/profile or BRCA2 mutation/profile; HRD based on BRCA1 or BRCA2 mutation and HRD based on BRCA1-like and/or BRCA2-like profile.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

Histologically or cytologically confirmed infiltrating breast cancer
Oligometastatic disease defined as one to three distant metastatic lesions, with or without primary tumor, local recurrence, or locoregional lymph node metastases, including the ipsilateral axillary, parasternal, and periclavicular regions. All lesions must be amenable to resection or radiotherapy with curative intent. Staging examinations must have included a PET-CT-scan and a MRI of the liver in case of liver metastases. Clustered lymph nodes that can be irradiated with curative intent in a single field are defined as a single lesion. Histologic or cytologic confirmation of at least one distant metastatic lesion is required.
No prior line of chemotherapy for metastatic disease (a maximum of 3 months of palliative endocrine therapy is allowed).
The tumor must be HER2-negative (either score 0 or 1 at immunohistochemistry or negative at in situ hybridization in case of score 2 or 3 at immunohistochemistry).
The tumor is deficient in homologous recombination and/or the patient has a deleterious germline BRCA1 or BRCA2 mutation.
At least stable disease of all tumor lesions after three courses of induction chemotherapy
Age ≥18 years
World Health Organisation (WHO) performance status 0 or 1
Adequate bone marrow function (ANC ≥1.0 x 109/l, platelets ≥100 x 109/l)
Adequate hepatic function (ALAT, ASAT and bilirubin ≤2.5 times upper limit of normal)
Adequate renal function (creatinine clearance ≥60 ml/min)
If clinically recommended echocardiography, MUGA, or MRI to evaluate if LVEF ≥50%;
Signed written informed consent
Able to comply with the protocol

Exclusion Criteria:

No malignancy other than breast cancer, unless treated with curative intent without the use of chemotherapy or radiation therapy
No current pregnancy or breastfeeding. Women of childbearing potential must use adequate contraceptive protection.
No concurrent anti-cancer treatment or investigational drugs