Multicenter open-label, phase II trial, to evaluate the efficacy and safety of nal-IRI for progressing brain metastases in patients with HER2-negative breast cancer.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Medica Scientia Innovation Research S.L.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

28 Apr 2017 → 2 Apr 2025

Decision date (initial)

2024-10-14

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Baxalta

External identifiers

EU CT number

2024-514999-41-00

EudraCT number

2016-002689-30

ClinicalTrials.gov

NCT03328884

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To assess the efficacy -defined as intracranial (IC) objective response rate (ORR)- of nal-IRI in patients with HER2-negative metastatic breast cancer who have documented central nervous system (CNS) progression following WBRT, SRS and/or surgery, as determined by the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria with central confirmation by a volumetric parameter.

Secondary objectives 3

1. To assess the efficacy for IC, extracranial (EC), and overall lesions -defined as ORR, clinical benefit rate (CBR) at 12 weeks, disease control rate (DCR), progression-free survival (PFS), time to response (TTR), duration of response (DoR), maximum tumor shrinkage (MTS), and overall survival- of nal-IRI in patients with progressing brain metastases and in all patients with CNS involvement.
2. Safety and tolerability in all patients with CNS involvement.
3. To assess the efficacy for overall lesions -defined as ORR, clinical benefit rate (CBR) at 12 weeks, disease control rate (DCR), progression-free survival (PFS), time to response (TTR), duration of response (DoR), maximum tumor shrinkage (MTS), and overall survival- of nal-IRI in patients with stable brain metastases.

Conditions and MedDRA coding

HER2 negative metastatic breast cancer (MBC) with nervous system involvement and measurable metastases

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. Female or male patients > 18 years
2. Patients must have sufficient organ and marrow function as defined below: a. Hematopoietic parameters: i. Absolute neutrophil count (ANC) ≥ 1,5 x 109 /L ii. Platelets ≥ 100 x 109 /L iii. Haemoglobin ≥ 9 mg/dL b. Hepatic parameters: i. Total bilirubin ≤ 1.5 mg/dL ii. AST (SGOT)/ALT (SGPT) ≤ 2.5 X institutional upper limit of normal c. Renal parameters: i. Creatinine ≤ 1.5 X institutional upper limits of normal, OR ii. Creatinine clearance ≥ 60 mL/min/1.73 m2 for pts w/ creatinine levels > institutional normal.
3. Patients must have a diagnosis of metastatic breast cancer.
4. Patients should have been pretreated with taxanes at any time prior to the study enrolment if not formally contraindicated.
5. At least one prior chemotherapy regimen for advanced disease.
6. Evidence of new brain metastases and/or stable or progressive brain metastases following previous WBRT and/or SRS and/or surgery.
7. At least one brain lesion needed to be measurable for new and progressive metastases (≥10 mm on T1-weighted, gadolinium-enhanced magnetic resonance imaging). For stable brain metastases at least one extracerebral lesion need to be measurable.
8. HER2 negative breast cancer defined as 0 - 1+ by immunohistochemistry or FISH negative result.
9. ECOG performance status <2.
10. Life expectancy >12 weeks.
11. Participants of childbearing potential must agree to use at least efficient contraception method (even though it is recommendable for them to use a highly effective method) prior to study entry and for the duration of study participation as well as a negative serum pregnancy test within 7 days of study enrolment and at the end of treatment visit.
12. Ability to understand and the willingness to sign a written informed consent.

Exclusion criteria 15

1. Patients must not have previously received nal-IRI or any other form of irinotecan, conventional or liposomal.
2. Pregnant or lactating women.
3. Patients who have received prior anti-cancer treatment with chemotherapy, endocrine therapy, immunotherapy or radiotherapy within 3 weeks (6 weeks for nitrosoureas or mitomycin-C) prior to starting study treatment.
4. Radiation therapy encompassing more than 30% of bone marrow.
5. Significant chronic gastrointestinal disorder with diarrhea as a major symptom (i.e Crohn’s disease, ulcerative colitis, malabsorption, or grade ≥ 2 diarrhea of any etiology at baseline)
6. Have a serious concomitant systemic disorder (e.g. active infection including HIV, or cardiac disease) incompatible with the study (at the discretion of investigator), previous history of bleeding diathesis, or treatment with Sintrom or any anti-vitamin K.
7. Patients who have symptomatic lymphangitis, dyspnoea at rest or meningeal carcinomatosis. (Patients with asymptomatic involvement may be enrolled in the study.)
8. Patients must be recovered from any clinically relevant toxic effects of any prior surgery, radiotherapy or other therapy intended for the treatment of breast cancer. For peripheral neuropathy, up to CTCAE (v4.0) Grade 2 is acceptable for patients with pre-existing condition.
9. Patients may not be receiving any other investigational or anticancer agents while on the study.
10. History of other malignancies, which could affect compliance with the protocol or interpretation of the results. Patients with malignancies diagnosed more than 5 years prior to study day 1, adequately treated carcinoma in situ of the cervix or basal or squamous cell skin are generally eligible.
11. NYHA Class III or IV congestive heart failure, ventricular arrhythmias or uncontrolled blood pressure. Or known abnormal ECG with clinically significant abnormal findings.
12. Active infection or an unexplained fever >38.5°C (excluding tumoral fever), which in the physician’s opinion might compromise the patient’s health.
13. Patients with other significant disease or disorders that, in the Investigator's opinion, would exclude the patient from the study.
14. Current use or any use in the last two weeks of strong CYP3A-enzyme inducers/inhibitors and/or strong UGT1A inhibitors
15. Known hypersensitivity to any of the components of nanoliposomal irinotecan (nal-IRI), other liposomal irinotecan formulations or irinotecan.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. ORR-IC determined using modified RANO- BM criteria with central confirmation by a volumetric parameter in patients with progressive brain metastases. According to these criteria Complete response (CR) will be defined as the disappearance of all CNS target lesions, no new lesions, no corticosteroids; stable or improved clinically.
2. Partial response (PR) will be defined as a decreased of at least 30% in the sum longest diameter (LD) of CNS target lesions, taking as reference the baseline sum LD; no new lesions; no corticosteroids; stable or improved clinically). CR and PR (≥30% unidimensional reduction of CNS lesions) must be sustained for at least 4 weeks or centrally confirmed according to volumetric parameter (≥65% volumetric reduction of CNS lesions).

Secondary endpoints 11

1. ORR will be defined according to a volumetric parameter defined as the proportion of patients with a reduction in tumor burden (>65% volumetric reduction of CNS lesion(s) in the absence of increasing steroid use, progressive neurologic symptoms and/or signs or progressive extra CNS disease) and to RECIST 1.1 criteria. In patients with progressing brain metastases. The volumetric parameter will be centrally reviewed.
2. ORR will be defined as the percentage of patients who experience a CR, PR determined locally by the investigator, using RECIST criteria v.1.1 (for IC, EC, and overall lesions) in patients with progressing brain metastases and in all patients with CNS involvement.
3. CBR will be defined as the percentage of patients who experience a CR, PR or stable disease for at least 12 weeks determined locally by the investigator, using RANO-BM criteria (for IC lesions) and RECIST criteria v.1.1 (for IC, EC, and overall lesions) in patients with progressing brain metastases and in all patients with CNS involvement.
4. DCR will be defined as the percentage of patients who experience a CR, PR or stable disease determined locally by the investigator, using RANO-BM criteria (for IC lesions) and RECIST criteria v.1.1 (for IC, EC, and overall lesions) in patients with progressing brain metastases and in all patients with CNS involvement.
5. PFS will be defined as the time from treatment initiation to the first occurrence of disease progression or death from any cause, whichever occurs first, determined locally by the investigator, using RECIST criteria v.1.1 in patients with progressing brain metastases and in all patients with CNS involvement.
6. TTR will be defined as the time from treatment initiation to time of the first objective tumor response observed in patients who achieved a CR or PR, determined locally by the investigator, using RANO-BM criteria (for IC lesions) and RECIST criteria v.1.1 (for IC, EC, and overall lesions) in patients with progressing brain metastases and in all patients with CNS involvement.
7. DoR will be defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause, whichever occurs first, determined locally by the investigator, using RANO-BM criteria (for IC lesions) and RECIST criteria v.1.1 (for IC, EC, and overall lesions) in patients with progressing brain metastases and in all patients with CNS involvement.
8. MTS from baseline in the size of target tumor lesions, defined as the biggest decrease, or smallest increase if no decrease observed, determined locally by the investigator, using RANO-BM criteria (for IC lesions) and RECIST criteria v.1.1 (for IC, EC, and overall lesions) in patients with progressing brain metastases and in all patients with CNS involvement.
9. OS, defined as the time from treatment initiation to death from any cause, and determined locally by the investigator in patients with progressing brain metastases and in all patients with CNS involvement.
10. Patient safety and AEs will be determined locally by the investigator, using the CTCAE v4 in all patients with CNS involvement.
11. To assess ORR, CBR, DCR, TTR, DOR, PFS, and OS of nal-IRI in patients with stable brain metastases.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Medica Scientia Innovation Research S.L.

Sponsor organisation

Medica Scientia Innovation Research S.L.

Address

Carrer De Pere IV 128 3rd Floor

City

Barcelona

Postcode

08005

Country

Spain

Scientific contact point

Organisation

Medica Scientia Innovation Research S.L.

Contact name

Alicia García

Public contact point

Organisation

Medica Scientia Innovation Research S.L.

Contact name

Melissa Fernández

Locations

1 EU/EEA country · 15 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 9 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications