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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: carboplatin, thiotepa, and cyclophosphamide; Drug: chemotherapy (docetaxel, doxorubicin, cyclofosfamide, carboplatin, paclitaxel, gemcitabine)

• Study Type: Interventional
• Enrollment (Actual): 74
• Phase: Phase 3

Contacts and Locations

Study Locations

• Netherlands
  • Amsterdam, Netherlands, 1066 CX
    • NKI-AvL

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

1. Histologically or cytologically confirmed infiltrating breast cancer
2. 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.
3. No prior line of chemotherapy for metastatic disease (a maximum of 3 months of palliative endocrine therapy is allowed).
4. 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).
5. The tumor is deficient in homologous recombination and/or the patient has a deleterious germline BRCA1 or BRCA2 mutation.
6. At least stable disease of all tumor lesions after three courses of induction chemotherapy
7. Age ≥18 years
8. World Health Organisation (WHO) performance status 0 or 1
9. Adequate bone marrow function (ANC ≥1.0 x 109/l, platelets ≥100 x 109/l)
10. Adequate hepatic function (ALAT, ASAT and bilirubin ≤2.5 times upper limit of normal)
11. Adequate renal function (creatinine clearance ≥60 ml/min)
12. If clinically recommended echocardiography, MUGA, or MRI to evaluate if LVEF ≥50%;
13. Signed written informed consent
14. 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event free survival	time from randomization to local recurrence, second primary, distant recurrence or death, whichever comes first	assessed up to 120 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference in median overall survival	time from randomization to death from any cause	assessed up to 120 months
Difference in percentage of patients with grade >2 hematologic toxicity (CTCAE v4.0)	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 non-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 quality of life (EORTC QLQ-C30 v 3.0)	Difference in quality of life (EORTC QLQ-C30 v 3.0)	6 and 12 months post treatment
Difference in event free survival	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.	assessed up to 120 months

Collaborators and Investigators

• Sponsor: The Netherlands Cancer Institute
• Investigators: Principal Investigator: Gabe S Sonke, MD, NKI-AVL, Amsterdam

Study record dates

Study Major Dates

• Study Start: September 1, 2014
• Primary Completion (Anticipated): January 1, 2023
• Study Completion (Anticipated): October 1, 2026

Study Registration Dates

• First Submitted: June 14, 2012
• First Submitted That Met QC Criteria: July 19, 2012
• First Posted (Estimate): July 20, 2012

Study Record Updates

• Last Update Posted (Actual): October 12, 2022
• Last Update Submitted That Met QC Criteria: October 11, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: oligo metastatic; HRD deficiency
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Gemcitabine; Docetaxel; Cyclophosphamide; Carboplatin; Paclitaxel; Doxorubicin; Thiotepa
• Other Study ID Numbers: N12OLG; 2012-000838-19 (EudraCT Number)