Trial Title:
PIK3CA/PTEN-altered Advanced Breast Cancer Treated With MEN1611 Monotherapy or in Combination With Eribulin
NCT ID:
NCT05810870
Condition:
Breast Cancer
Advanced Breast Cancer
Metastatic Breast Cancer
Conditions: Official terms:
Breast Neoplasms
Conditions: Keywords:
Breast cancer
MEN1611
Eribulin
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Parallel Assignment
Intervention model description:
Multicenter, two-cohort, non-comparative, open-label, phase II clinical trial.
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
MEN1611
Description:
MEN1611 is a potent, orally bioavailable selective inhibitor of the class I
phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) with a novel structure which
exhibits a strong inhibitory activity especially against the PI3K catalytic subunit alpha
(PIK3CA), with potential antineoplastic activity. PI3K alpha inhibitor MEN1611
selectively binds to and inhibits PIK3CA and its mutated forms in the PI3K/Akt (protein
kinase B)/mammalian target of rapamycin (mTOR) pathway.
Arm group label:
Cohort A
Arm group label:
Cohort B
Intervention type:
Drug
Intervention name:
Eribulin
Description:
Eribulin mesylate (eribulin), a non-taxane inhibitor of microtubule dynamics of the
halichondrin class of antineoplastics, suppresses microtubule growth and sequesters
tubulin into nonfunctional aggregates, preventing mitotic spindle formation with
subsequent G2-M stop and apoptosis.
Arm group label:
Cohort A
Arm group label:
Cohort B
Other name:
HALAVEN, Eribulin mesylate
Summary:
The multicenter, two-cohort, non-comparative, open-label, phase II clinical trial SABINA
aims to analyze the safety and efficacy of MEN1611 in monotherapy and in combination with
eribulin, a non-taxane chemotherapy agent, in Hormone Receptor (HR)-known/Human
Epidermial Growth Factor Receptor 2 (HER2)-negative,
phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)/
Phosphatase and Tensin Homolog (PTEN)-altered, unresectable locally advanced or
metastatic metaplastic breast carcinoma (MpBC) patients.
A run-in phase for safety and tolerability of MEN1611 in combination with standard doses
of eribulin will be conducted as an initial step of the cohort A. This first step aims at
evaluating the dosing schedule of MEN1611, by analyzing the toxicity profile of the
combined regimen.
With the background of the first-in-human study (PA-001EU), the safe dose of MEN1611 has
been established as 48 mg orally BID (two intakes of 3 capsules of 16 mg each, for a
total daily dose of 96 mg MEN1611 free-base).
Detailed description:
This is a multicenter, two-cohort, non-comparative, open-label, phase II clinical trial
to assess:
- the efficacy of MEN1611 in combination with eribulin as determined by the clinical
benefit rate (CBR) in unresectable locally advanced or metastatic
HR-known/HER2-negative, PIK3CA/ PTEN-altered MpBC patients (Cohort A), and
- the efficacy of MEN1611 as monotherapy as determined by the objective response rate
(ORR) at 6 weeks in unresectable locally advanced or metastatic
HR-known/HER2-negative, PIK3CA/ PTEN-altered MpBC patients (Cohort B).
Upon meeting all selection criteria, 28 patients will be enrolled as follows:
- Cohort A: A run-in phase for safety and tolerability of MEN1611 in combination with
eribulin will be conducted in this patient population (N=3). A Steering Committee
decision/agreement is needed, after reviewing all toxicities, to expand this cohort
with 11 additional patients (up to N=14).
Cohort B will be run only if positive finding in Cohort A, defined as ≥ 6 patients
(42.9%) with achieved clinical benefit (CB) among 14 first recruited patients.
- Cohort B: Simon's two-stage minimax design. Stage I (N=7) will be initiated with
MEN1611 monotherapy. This cohort will be stopped for futility if no responders (no
complete response [CR] or partial response [PR]) are observed after 2 cycles among
the first 7 patients included. Otherwise, Cohort B will be expanded with 7
additional patients for Stage II (up to N=14).
Criteria for eligibility:
Criteria:
General inclusion criteria (cohort A and cohort B)
PRE-SCREENING PHASE
The following criteria must be met to be eligible to entry into the pre-screening:
1. Patient must be able to sign written pre-screening form prior to any molecular
determination during the pre-screening phase.
2. Being male or female aged ≥ 18 years.
3. Histological confirmed MpBC as per local assessment.
4. Known HR status according to the updated American Society of Clinical Oncology
(ASCO)/College of American Pathologists (CAP) 2020 guidelines and HER2-negative
breast cancer (BC) as per ASCO/CAP 2018 criteria based on local testing on the most
recently analyzed biopsy.
5. Prior treatment with at least one, but no more than four, prior lines of systemic
therapy for advanced disease. Earlier adjuvant or neoadjuvant therapy for more
limited disease will be considered as one of the required prior regimens if the
development of unresectable locally advanced metastatic disease occurred within a
6-month period after completion of chemotherapy.
6. No prior treatment with a PI3K/AKT/mTOR inhibitor (cohorts A and B), nor with
eribulin (only for patients in cohort A).
7. Patient must consent to give a tumor sample or/and a blood sample for testing of the
prior mentioned alterations (or if needed and deemed safe by the investigator, able
to provide a fresh tumor sample).
8. Unknown PIK3CA mutational and PTEN loss status.
SCREENING PHASE
Patients must meet inclusion criteria 2 to 7 of the pre-screening phase and the
following inclusion criteria of the screening phase to be eligible for enrollment
into the Study:
9. Patient must be able to sign written main informed consent form (ICF) prior to
participation in any Study-related activities.
10. Eastern Cooperative Oncology Group (ECOG) performance status must be 0 or 1 which
the Investigator believes is stable at the time of screening.
11. Life expectancy greater or equal to 12 weeks.
12. Unresectable locally advanced/metastatic MpBC documented by computed tomography (CT)
scan or magnetic resonance imaging (MRI), that is not amenable to resection with
curative intent.
13. Patient has a PIK3CA mutation confirmed by MEDSIR's designated central lab,
determined in the pre-screening phase or patient has a pathology report confirming
PIK3CA mutant status by a certified laboratory (using validated PIK3CA mutation
assay) either from tissue or blood
And/or
Patient has evidence of PTEN loss by immunohistochemistry (IHC) confirmed by
MEDSIR's designated central lab in the pre-screening phase or patient has a
pathology report confirming PTEN loss by a certified laboratory, preferably on the
most recent available tumor sample.
Note:. PI3KCA mutations should have been evaluated at least at hot spots, E542, E545
and H1047. PTEN staining should have been evaluated by assessing both intensity of
staining and percentage of positive cells. Both nuclear and cytoplasmic staining
should be evaluated. Staining of normal cells such as benign breast epithelium,
stromal cells and/or endothelial cells should have been evaluated as an internal
control. Any tumor nuclear or cytoplasmic staining showing similar intensity with
internal control cells should have been considered positive staining (no PTEN loss).
Complete lack of staining or faint staining (cytoplasmic or nuclear) in up to 50% of
tumor cells should have been considered as PTEN loss. If there was no staining in
internal control cells, the staining should have been considered inconclusive.
14. Patients with clinically stable metastatic CNS tumors who are not receiving steroid
therapy or anticonvulsant at baseline are eligible if:
1. Stereotactic radiotherapy ³ 7 days prior to initiation of study treatment.
2. Whole-brain radiotherapy ³ 7 days prior to initiation of study treatment.
3. Neurosurgical resection ³ 28 days prior to initiation of study treatment.
15. Resolution of all acute toxic effects of prior anti-cancer therapy to grade ≤ 1 as
determined by the US National Cancer Institute-Common Terminology Criteria for
Adverse Events (NCI-CTCAE) version 5.0 (v.5.0).
Note: Except for alopecia or other toxicities not considered a safety risk for the
patient at investigator's discretion.
16. Available archival tumor sample (FFPE tissue) of the most recent biopsy/surgery
since last progression.
Note: Subjects for whom the most recent tumor biopsy since last progression could
not be obtained (e.g., inaccessible tumor or subject safety concern) may submit
archival pathological material from either metastatic or primary sites.
17. Adequate hematologic and organ function within 14 days before the first Study
treatment on Day 1 of Cycle 1, defined by the following:
1. Hematological (without platelet, red blood cell transfusion, and/or granulocyte
colony-stimulating factor support within 7 days before first Study treatment
dose): White blood cell (WBC) count > 3.0 x 109/L, absolute neutrophil count
(ANC) ≥ 1.5 x 109/L, platelet count ≥ 100.0 x109/L, and hemoglobin ≥ 9.0 g/dL
(≥ 5.6 mmol/L).
2. Hepatic: Serum albumin ≥ 3 g/dL; total bilirubin ≤ 1.5 times the upper limit of
normal (ULN) (≤ 3 x ULN in the case of Gilbert's disease); aspartate
transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 × ULN (in the case of
liver metastases ≤ 5 × ULN); alkaline phosphatase (ALP) ≤ 2 × ULN (≤ 5 × ULN in
the case of liver and/or bone metastases).
Note: If total bilirubin is increased, assessment of direct bilirubin levels is
recommended.
3. Renal: serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 mL/min based
on Cockcroft-Gault glomerular filtration rate estimation.
e. Urinalysis: including dipstick (specific gravity, pH, glucose, protein, ketones,
and blood) and microscopic examination (sediment, RBCs, WBCs, casts, crystals,
epithelial cells, and bacteria).
18. For women of childbearing potential: agreement to remain abstinent (must refrain
from heterosexual intercourse) or use highly effective contraceptive methods, or two
effective contraceptive methods, as defined in the CSP, during the treatment period
and for at least 7 months after the last dose of Study treatment, whichever is
longer. Women of childbearing potential must have a negative serum pregnancy test
within 7 days before Study treatment initiation and must agree to refrain from
donating eggs during the entire Study treatment period and for 3 months after the
last administration of the Study drug.
19. Being male subjects, surgically sterile or having agreed with true abstinence (must
refrain from heterosexual intercourse), or whose female partners are willing to
agree with true abstinence or use barrier contraceptive measures mentioned above
during the entire Study treatment period and for 7 months after the last
administration of the Study drug. Males must agree to refrain from donating sperm
during the entire Study treatment period and for 3 months after the last
administration of the Study drug.
20. Patient must be accessible for treatment and follow-up.
Cohort A specific inclusion criteria
1. Measurable, or non-measurable but evaluable, disease as defined by the local site
Investigator as per Response Evaluation Criteria in Solid Tumors (RECIST) version
1.1 (v1.1) criteria.
Note: Patients with bone lesions as the only sites of metastatic disease are eligible.
Cohort B specific inclusion criteria
1. Measurable disease as defined by RECIST v1.1 criteria.
Note: Patients with lytic bone lesions or mixed lytic-blastic lesions as the only sites
of metastatic disease, with identifiable soft tissue components, are eligible if the soft
tissue component meets the definition of measurability.
Exclusion criteria:
Any patient meeting ANY of the following criteria will be excluded from the Study:
1. Current participation in another therapeutic clinical trial.
2. Extra-cranial radiotherapy or limited-field palliative radiotherapy within 7 days
prior to Study enrolment, or patients who have not recovered from
radiotherapy-related toxicities to baseline or grade ≤ 1 and/or from whom ≥ 25% of
the bone marrow has been previously irradiated.
3. Major surgery (defined as requiring general anesthesia) or significant traumatic
injury within 21 days of start of Study drug, or patients who have not recovered
from the side effects of any major surgery.
4. Patient with a concurrent malignancy or malignancy within 5 years of Study
enrollment except for carcinoma in situ of the cervix, non-melanoma skin carcinoma,
or stage I uterine cancer.
Note: For other cancers considered to have a low risk of recurrence, discussion with
the Medical Monitor is required.
5. Treatment with approved chemotherapy/immunotherapy/ targeted agents within 21 days
prior to initiation of Study, or treatment with an investigational cancer therapy
for 21 days or 5 half-lives (whichever is longer) prior to initiation of any Study
treatment.
6. Patient with cerebrovascular accident or transient ischemic attack within 6 months
prior to the start of any Study treatment.
7. Congenital long QT syndrome or screening QT interval corrected using Fridericia's
formula (QTcF) > 480 milliseconds.
8. Patient with an active cardiac disease or a history of cardiac dysfunction or
conduction abnormalities including any of the following:
- Unstable angina pectoris or documented myocardial infarction within 6 months
prior to Study entry.
- Symptomatic pericarditis.
- Documented congestive heart failure (New York Heart Association functional
classification III- IV).
- Left ventricular ejection fraction (LVEF) < 50% as determined by multiple gated
acquisition (MUGA) scan or echocardiogram (ECHO).
- Ventricular arrhythmias except for benign premature ventricular contractions.
- Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled
with medication.
- Conduction abnormality requiring a pacemaker.
- Other cardiac arrhythmia not controlled with medication.
9. Patient with uncontrolled hypertension.
10. Uncontrolled diabetes mellitus (glycated haemoglobin [HbA1c] >7%) and/or fasting
plasma glucose (FPG) >120 mg/dL or 6.7 mmol/L.
Note: Patients who have DM adequately managed regardless FPG or HbA1c may be
consider eligible as per the Medical Monitor assessment and criteria.
11. Known concurrent severe and/or uncontrolled concomitant medical conditions (i.e.
influenza or any other active infections) that could cause unacceptable safety risks
or compromise compliance with the protocol.
12. Known active or uncontrolled pulmonary dysfunction.
13. Current known infection with human immunodeficiency virus (HIV), hepatitis B virus
(HBV), or hepatitis C virus (HCV). Patients with past HBV infection or resolved HBV
infection (defined as having a negative hepatitis B surface antibody [HBsAg] test
and a positive hepatitis B core antibody [HBcAb] test, accompanied by a negative HBV
DNA test) are eligible. Patients positive for HCV antibody are eligible only if
polymerase chain reaction (PCR) is negative for HCV RNA.
14. Known hypersensitivity reaction to any investigational or therapeutic compound or
their incorporated substances.
15. Patient with serious and/or unstable pre-existing psychiatric or neurologic illness
or other conditions that could interfere with subject safety.
16. History of significant gastrointestinal disease, including but not limited to
abdominal fistula, gastrointestinal perforation or other malabsorption syndromes
that would impact on drug absorption. Grade ≥2 diarrhea should resolve at least 7
days prior to the start of any Study treatment.
17. Subject receiving chronic treatment with steroids, as immunosuppressant, or another
immunosuppressive agent.
18. Subject receiving treatment with drugs known to be moderate and strong inhibitors or
inducers of isoenzyme CYP3A as well as moderate or strong inducers of CYP1A2 within
2 weeks of the first administration of MEN1611.
19. Breastfeeding or pregnancy as determined by a serum pregnancy test (β-HCG) at
screening, prior to the administration of MEN1611 either in monotherapy or in
combination with eribulin. Since β-HCG over expression can be also elevated in some
tumor types, a positive result should be confirmed with a validated alternative test
(e.g., ultrasound).
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Hospital Universitario Clínico San Cecilio de Granada
Address:
City:
Granada
Zip:
18016
Country:
Spain
Status:
Recruiting
Contact:
Last name:
Isabel Blancas, MD
Investigator:
Last name:
Isabel Blancas
Email:
Principal Investigator
Facility:
Name:
Hospital Universitario Virgen del Rocio
Address:
City:
Sevilla
Zip:
41013
Country:
Spain
Status:
Recruiting
Contact:
Last name:
Manuel Ruiz Borrego, MD
Investigator:
Last name:
Manuel Ruiz Borrego
Email:
Principal Investigator
Facility:
Name:
Hospital Universitario Marqués de Valdecilla
Address:
City:
Santander
Zip:
39008
Country:
Spain
Status:
Not yet recruiting
Contact:
Last name:
Carmen Hinojo
Investigator:
Last name:
Carmen Hinojo
Email:
Principal Investigator
Facility:
Name:
Centro Oncológico de Galicia
Address:
City:
A Coruña
Zip:
15009
Country:
Spain
Status:
Not yet recruiting
Contact:
Last name:
Margarita Amenedo
Investigator:
Last name:
Margarita Amenedo
Email:
Principal Investigator
Facility:
Name:
Hospital Universitario de Torrejón
Address:
City:
Torrejón De Ardoz
Zip:
28850
Country:
Spain
Status:
Recruiting
Contact:
Last name:
Magda Palka, MD
Investigator:
Last name:
Magda Palka, MD
Email:
Principal Investigator
Facility:
Name:
Onkologikoa
Address:
City:
San Sebastián
Zip:
20014
Country:
Spain
Status:
Recruiting
Contact:
Last name:
Ainhara Lahuerta Martinez, MD
Investigator:
Last name:
Ainhara Lahuerta Martinez, MD
Email:
Principal Investigator
Facility:
Name:
CHUVI - Complejo Hospitalario Universitario de Vigo
Address:
City:
Vigo
Zip:
36312
Country:
Spain
Status:
Recruiting
Contact:
Last name:
Isaura Fernández Pérez, MD
Contact backup:
Last name:
Maria Jose Villanueva
Investigator:
Last name:
Isaura Fernández Pérez
Email:
Principal Investigator
Facility:
Name:
Hospital Clínic i Provincial de Barcelona
Address:
City:
Barcelona
Zip:
08036
Country:
Spain
Status:
Not yet recruiting
Contact:
Last name:
Francesco Schettini
Investigator:
Last name:
Francesco Schettini
Email:
Principal Investigator
Facility:
Name:
Institut Català d' Oncologia L'Hospitalet (ICO)
Address:
City:
Barcelona
Zip:
08907
Country:
Spain
Status:
Recruiting
Contact:
Last name:
Agostina Stradella
Investigator:
Last name:
Agostina Stradella
Email:
Principal Investigator
Facility:
Name:
Hospital Universitari Vall D'Hebron
Address:
City:
Barcelona
Country:
Spain
Status:
Recruiting
Contact:
Last name:
Esther Zamora
Investigator:
Last name:
Esther Zamora
Email:
Principal Investigator
Facility:
Name:
Hospital Clínico San Carlos
Address:
City:
Madrid
Zip:
28040
Country:
Spain
Status:
Not yet recruiting
Contact:
Last name:
Jose Ángel García Sáenz
Investigator:
Last name:
Jose Ángel García Sáenz
Email:
Principal Investigator
Facility:
Name:
Hospital Beata María Ana
Address:
City:
Madrid
Country:
Spain
Status:
Recruiting
Contact:
Last name:
Patricia Cortez, MD
Investigator:
Last name:
Patricia Cortez
Email:
Principal Investigator
Facility:
Name:
Instituto Valenciano de Oncología (IVO)
Address:
City:
Valencia
Zip:
46009
Country:
Spain
Status:
Recruiting
Contact:
Last name:
Angel Guerrero, MD
Investigator:
Last name:
Angel Guerrero, MD
Email:
Principal Investigator
Start date:
May 24, 2023
Completion date:
July 2027
Lead sponsor:
Agency:
MedSIR
Agency class:
Other
Collaborator:
Agency:
Menarini Group
Agency class:
Industry
Source:
MedSIR
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05810870
