Evaluation of the Efficacy and Safety of Nal-IRI for Progressing Brain Metastases in Breast Cancer Patients

Breast Cancer Metastatic Clinical Trial

— Phenomenal  

Official title:

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 (The Phenomenal Study)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03328884
• Other study ID #: MedOPP107
• Secondary ID: 2016-002689-30
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: May 2, 2017
• Est. completion date: June 2, 2025

Study information

• Verified date: September 2023
• Source: MedSIR
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Multicenter open-label, phase II trial, to evaluate the efficacy and safety of nal-IRI in patients with HER2-negative breast cancer, who have documented Central Nervous System (CNS) progression following Whole Brain Radio Therapy (WBRT), Stereotactic Radiosurgery (SRS) and/or surgery, as determined by the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria.

Description:

This is an international, prospective, open-label, multicenter, single arm, two-stage Simon Design phase II clinical trial, with the primary objective of assessing the efficacy of nal-IRI single agent in a cohort of HER2-negative metastatic breast cancer (MBC) patients with CNS involvement. Eligible patients will have histologically proven diagnosis of adenocarcinoma of the breast, they must have progressed to at least one prior chemotherapy regimen in the metastatic setting and must have been progressed in CNS to previous local treatment (Surgery and/or WBRT and/or SRS) showing at least one measurable lesion in the CNS (symptomatic meningeal carcinomatosis is not permitted). Eligible patients must have been previously received at least treatment with taxanes (either in the neo/adjuvant or in the metastatic scenario). Patients could not be eligible if they are candidates for a local treatment with a radical intention. Patients will be accrued in a two-stage design. Considering a drop-out rate of 10%, the accrual goal will be a total of 63 patients in both stages (first stage will include 23 evaluable patients and the second stage will include 33 more evaluable patients).

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 55
• Est. completion date: June 2, 2025
• Est. primary completion date: August 31, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Female or male patients > 18 years

2. Patients must have a diagnosis of metastatic breast cancer.

3. Patients should have been pretreated with taxanes at any time prior to the study enrolment if not formally contraindicated.

4. At least one prior chemotherapy regimen for advanced disease.

5. Evidence of new brain metastases and/or stable or progressive brain metastases following previous WBRT and/or SRS and/or surgery.

6. 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.

7. HER2 negative breast cancer defined as 0 - 1+ by immunohistochemistry or FISH negative result.

8. ECOG performance status <2.

9. Life expectancy >12 weeks.

10. Patients must have sufficient organ and marrow function as defined below:

a. Hematopoietic parameters: i. Absolute neutrophil count = 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.

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:

1. Patients must not have previously received nal-IRI or any other form of irinotecan, conventional or liposomal.

2. 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.

3. Radiation therapy encompassing more than 30% of bone marrow.

4. 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)

5. 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.

6. Patients who have symptomatic lymphangitis, dyspnoea at rest or meningeal carcinomatosis. (Patients with asymptomatic involvement may be enrolled in the study.)

7. 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.

8. Patients may not be receiving any other investigational or anticancer agents while on the study.

9. 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.

10. Pregnant or lactating women.

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.

Related Conditions & MeSH terms

• Brain Neoplasms
• Breast Cancer Metastatic
• Breast Neoplasms

Intervention

Drug:
• Irinotecan Hydrochloride
nal-IRI (nanoliposomal irinotecan, also known as MM-398 and PEP02) is irinotecan hydrochloride, (also known as CPT-11) a topoisomerase 1 inhibitor, encapsulated in a liposome drug delivery system. nal-IRI will be administered with a fixed dose of 60 mg/m2 on D1 of a 14-day cycle in monotherapy.

Locations

Country	Name	City	State
Spain	ICO	Badalona
Spain	IOB Institute of Oncology - Quirón Barcelona	Barcelona
Spain	Hospital Universitario Clinico San Cecilio	Granada
Spain	Hospital Universitario Virgen de Las Nieves	Granada
Spain	H. Ruber Juan Bravo	Madrid
Spain	Hospital Clínico San Carlos	Madrid
Spain	Hospital Doce de Octubre	Madrid
Spain	Hospital Universitario Ramón y Cajal	Madrid
Spain	MD Anderson Madrid	Madrid
Spain	Hospital Clínico Virgen de la Victoria	Málaga
Spain	Hospital Universitari Son Espases	Palma De Mallorca
Spain	Son Llatzer	Palma De Mallorca
Spain	Sant Joan de Reus	Reus
Spain	Hospital Universitario Virgen del Rocío	Sevilla
Spain	IVO	Valencia
Spain	H. Miguel Servet	Zaragoza

Sponsors (1)

Lead Sponsor	Collaborator
MedSIR

Country where clinical trial is conducted

Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	CNS Overall Response Rate (ORR)	The efficacy of nal-IRI will be measured in terms of CNS ORR, defined as per RANO-BM criteria. According to these criteria Complete Response (CR) will be defined as the disappearance of all CNS target lesions sustained for at least 4 weeks; no new lesions, no corticosteroids; stable or improved clinically. Partial Response (PR) will be defined as a decrease of at least 30% in the sum longest diameter (LD) of CNS target lesions, taking as reference the baseline sum LD, sustained for at least 4 weeks; no new lesions; no corticosteroids; stable or improved clinically.	From Baseline up to 80 weeks after patient entry
Secondary	CNS disease stabilization on week 12	CNS clinical benefit rate (CBR) at week 12 will be defined as the percentage of patients who experience a CR, PR or Stable Disease (SD) for at least 12 weeks assessed by the modified Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v.1.1) criteria.	From Baseline up to 12 weeks after patient entry
Secondary	ORR, according to a volumetric parameter, and to the RECIST v.1.1 criteria	ORR according to a volumetric parameter. For this objective, PR will be defined as > 65% volumetric reduction of CNS lesion(s) and to the RECIST v.1.1 criteria. The volumetric parameter will be centrally reviewed.	From Baseline up to 80 weeks after patient entry
Secondary	CBR	The percentage of patients who experience a CR, PR or SD for at least 24 weeks and assessed by the RECIST v.1.1 criteria.	3 years
Secondary	Safety profile of nal-IRI in this population by Common Terminology Criteria for Adverse Events version 4 (CTCAE v.4) criteria	This study will consider the National Cancer Institute (NCI) CTCAE v.4 criteria grade 3 and 4 adverse events (AEs) and serious AEs (SAEs) in order to assess the safety and tolerability objectives.	3 years
Secondary	Progression-Free Survival (PFS)	PFS will be defined as the time from the first dose of treatment to death or disease progression as assessed by the Investigator per RECIST v1.1 criteria.	3 years
Secondary	Overall Survival (OS)	OS will be defined as the time from the first dose of treatment to death for any cause.	3 years
Secondary	Disease Control Rate	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.	18 months after last patient included
Secondary	TTR	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.	From treatment initiation to time of the first objective tumor response in patients with CR or PR,
Secondary	DoR	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.	time from the first occurrence of a documented objective response to disease progression or death
Secondary	MTS	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.	From baseline