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

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)

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.

Study Overview

• Status: Recruiting
• Conditions: Breast Cancer Metastatic
• Intervention / Treatment: Drug: Irinotecan Hydrochloride

Detailed 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).

• Study Type: Interventional
• Enrollment (Estimated): 63
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Alicia Garcia; Phone Number: +34 932 214 135; Email: alicia.garcia@medsir.org
• Study Contact Backup: Name: Marta Beltran; Phone Number: +34 672 685 738; Email: marta.beltran@medsir.org

Study Locations

• Spain
  • Badalona, Spain
    • Recruiting
    • ICO
    • Contact: Mireia Margeli, MD
  • Barcelona, Spain
    • Recruiting
    • IOB Institute of Oncology - Quirón Barcelona
    • Contact: Jesus Soberino, MD
  • Cáceres, Spain
    • Withdrawn
    • Hospital San Pedro Alcántara
  • Girona, Spain
    • Withdrawn
    • ICO
  • Granada, Spain, 18014
    • Recruiting
    • Hospital Universitario Virgen de Las Nieves
    • Contact: Encarnación Gonzalez, MD
  • Granada, Spain, 18016
    • Recruiting
    • Hospital Universitario Clínico San Cecilio
    • Contact: Maria Isabel Blancas, MD
  • Madrid, Spain
    • Recruiting
    • Hospital Universitario Ramón y Cajal
    • Contact: Maria Fernandez, MD
  • Madrid, Spain
    • Recruiting
    • Hospital Clínico San Carlos
    • Contact: Jose Angel, MD
  • Madrid, Spain
    • Recruiting
    • MD Anderson Madrid
    • Contact: Maria Isabel Calvo, MD
  • Madrid, Spain
    • Recruiting
    • Hospital Doce de Octubre
    • Contact: Laura Lema, MD
  • Madrid, Spain
    • Completed
    • H. Ruber Juan Bravo
  • Málaga, Spain
    • Recruiting
    • Hospital Clínico Virgen de la Victoria
    • Contact: Emilio Alba, MD
  • Palma De Mallorca, Spain
    • Recruiting
    • Hospital Universitari Son Espases
    • Contact: Neus Ferrer, MD
  • Palma De Mallorca, Spain
    • Recruiting
    • Son Llatzer
    • Contact: Maria Galan, MD
  • Reus, Spain
    • Recruiting
    • Sant Joan de Reus
    • Contact: Kepa Amillano, MD
  • Sabadell, Spain
    • Withdrawn
    • Corporacio Sanitaria Parc Tauli
  • Santiago De Compostela, Spain
    • Withdrawn
    • CHUS
  • Sevilla, Spain
    • Recruiting
    • Hospital Universitario Virgen del Rocio
    • Contact: Manuel Ruiz, MD
  • Valencia, Spain
    • Recruiting
    • IVO
    • Contact: Salvador Blanch, MD
  • Zaragoza, Spain
    • Recruiting
    • H. Miguel Servet
    • Contact: Antonio Anton, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: nal-IRI; This is a single arm study. After signing the informed consent form, patients will start treatment with nal-IRI. nal-IRI will be administered at a fixed dose of 60 mg/m2 on D1 of a 14-day cycle in monotherapy.	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.; Other Names: nal-IRI

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
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
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
Overall Survival (OS)	OS will be defined as the time from the first dose of treatment to death for any cause.	3 years
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
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,
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
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

Collaborators and Investigators

• Sponsor: MedSIR
• Investigators: Principal Investigator: Javier Cortes, Hospital Universitario Ramón y Cajal

Study record dates

Study Major Dates

• Study Start (Actual): May 2, 2017
• Primary Completion (Actual): August 31, 2018
• Study Completion (Estimated): March 31, 2024

Study Registration Dates

• First Submitted: March 17, 2017
• First Submitted That Met QC Criteria: October 30, 2017
• First Posted (Actual): November 1, 2017

Study Record Updates

• Last Update Posted (Estimated): March 4, 2024
• Last Update Submitted That Met QC Criteria: February 28, 2024
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Central Nervous System Neoplasms; Nervous System Neoplasms; Breast Neoplasms; Brain Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase Inhibitors; Topoisomerase I Inhibitors; Irinotecan
• Other Study ID Numbers: MedOPP107; 2016-002689-30 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: It is not planned

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No