Palbociclib and Binimetinib in Advanced Triple Negative Breast Cancer

NCT04494958

Last updated date
Study Location
Hospital Universitari Arnau de Vilanova de Lleida
Lleida, , 25198, Spain
Contact
+34917328000

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Eligibility Criteria
condition
The disease, disorder, syndrome, illness, or injury that is being studied.
Triple Negative Breast Cancer
Sex
Female
Age
Pediatric Trials: 0-17 Years
Adult Trials: 18+ Years
18 + years
Inclusion Criteria
The factors, or reasons, that allow a person to participate in a clinical study.
Show details

1. Women >18 years-old.

2. Diagnostic of metastatic or locally advanced non-resectable TNBC.

3. Patient that have received up to two previous lines of therapy for metastatic TNBC and failed to last treatment. Previous treatments can be of any nature (chemotherapy, immunotherapy, antiangiogenics, experimental therapy, etc.).

4. Availability of tumor tissue for ERK and CDK4/6 testing is mandatory prior to study inclusion, preferably obtained after last treatment or the most recent sample as possible (from metastatic site or first diagnosis according to sample availability). If the patient has not a tumor sample available prior to study inclusion, the patient will not be allowed to participate in the study.

5. Ability to understand and signing of the written patient information/informed consent form (PIS/ICF) for ERK and CDK4/6 testing. ERK and CDK4/6 testing will be performed centrally at CNIO.

6. Ability to understand and signing the written PIS/ICF for study treatment eligibility. Signed informed consent form must be available before any studyspecific procedure for the respective study parts may begin.

7. Positivity for ERK and/or CDK4/6, defined as showing an H-score above the top-quartile according to published definitions [1].

8. ECOG performance status of 0-1.

9. Evaluable disease according to RECIST 1.1 criteria.

10. Life expectancy >24 weeks.

11. Adequate bone marrow, liver and renal function as assessed by laboratory requirements conducted within 7 days before first study drug administration:

1. Absolute neutrophil count (ANC) ≥ 1.500/mm3 (without granulocyte colony-stimulating factor support within 2 weeks before the first study drug administration)

2. Hemoglobin ≥ 9 g/dL (without transfusion or erythropoietin within 4 weeks before the first study drug administration)

3. Platelet count ≥ 100.000/mm3 (without transfusion within 2 weeks before the first study drug administration)

4. Total bilirubin ≤ 2 X the upper limit of normal (ULN).

5. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 X ULN (≤ 5 times ULN for patients with liver metastases)

6. Glomerular filtration rate (GFR) > 50 mL/min/1.73 m2 according to the modification of diet in renal disease (MDRD) abbreviated formula.

12. Patients must have recovered to ≤ Grade 1 in terms of toxicity from prior treatments (excluding neuropathy which can be ≤ Grade 2, and alopecia).

13. Patients must be able to take oral medications.

14. Patients must have adequate cardiac function, defined as:

1. Left ventricular ejection fraction (LVEF) > 50% as determined by echocardiogram or multigated acquisition scan (MUGA).

2. QTc < 480 msec.

15. Negative serum pregnancy test in women of childbearing potential (performed within 7 days before the first treatment). Negative results must be available before the first study drug administration.

16. Women of reproductive potential must agree to use adequate contraception when sexually active. This applies for the time period since the signature of the informed consent form and until at least 1 month after the last study drug administration. The definition of adequate contraception will be based on the judgment of the investigator and on local requirements. Acceptable methods of contraception include, but are not limited to, (i) condoms (male or female) with or without a spermicidal agent; (ii) diaphragm or cervical cap with spermicide; (iii) intra-uterine device; (iv) hormone-based contraception.Zoledronic acid or denosumab started prior to trial registration is allowed, but in case they are required after initiation of trial procedures, adequate justification is required.

Exclusion Criteria
The factors, or reasons, that prevent a person from participating in a clinical study.
Show details


1. Participants who have had chemotherapy, radiotherapy, or major surgery within 2 weeks
(6 weeks for nitrosoureas or mitomycin C) prior to entering the study.


2. Patients that received during the metastatic disease setting any of the study drugs,
palbociclib or binimetinib.


3. Participants receiving any other study agents concurrently with the study drugs.
Zoledronic acid or denosumab for bone metastases, started at least 15 days prior to
enrollment are allowed.


4. Participants with symptomatic brain metastases that require chronic steroids. Patients
with a history of brain metastases are permitted to enroll as long as they have been
treated, are off of steroids, and have been stable for a minimum of one month on
imaging.


5. Irradiation of single lesions in the last 28 days prior to trial recruitment, if it is
the only location of the disease and it has not progressed. Patients with radiated
single lesions that has progressed are allowed.


6. Concurrent use of strong CYP3A4 inhibitors/inducers is prohibited due to drug-drug
interactions with palbociclib. Moderate CYP3A4 inhibitors/inducers should be used with
caution.


7. Uncontrolled intercurrent illness including, but not limited to:


1. ongoing or active infection requiring systemic treatment


2. symptomatic congestive heart failure


3. cardiac arrhythmia


4. psychiatric illness/social situations that would limit compliance with study
requirements


5. hypertension, defined as systolic blood pressure > 160 mmHg despite medical
management


6. myocardial infarction, unstable angina, coronary artery bypass grafting, coronary
angioplasty, or stenting < 6 months prior to screening


8. History of QT syndrome, Brugada syndrome, known history of QTc prolongation, or
Torsades de Pointes.


9. History of Gilbert's syndrome.


10. History of neuromuscular disorders that are associated with elevated CK (e.g.
inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal
muscular atrophy).


11. Previous or concurrent cancer except:


1. cervical carcinoma in situ


2. treated basal-cell carcinoma or squamous cell skin cancer c. any other cancer
curatively treated > 3 years before the first study drug administration


12. Malabsorption syndrome or uncontrolled nausea, vomiting, or diarrhea that may
interfere with the absorption of oral study medication in the opinion of the
investigator.


13. Pregnant women or breast-feeding.


14. Known HIV-positive individuals on combination antiretroviral therapy.


15. Active hepatitis B virus (HBV; chronic or acute; defined as having a known positive
hepatitis B surface antigen [HBsAg] test at the time of screening) or hepatitis C
infection requiring treatment.


1. Patients with past HBV infection or resolved HBV infection (defined as the
presence of hepatitis B core antibody [HBcAb] and absence of HBsAg) are eligible
if HBV DNA is negative.


2. Patients positive for hepatitis C virus (HCV) antibody are eligible only if
polymerase chain reaction is negative for HCV RNA.


16. Any condition that in the opinion of the investigator would interfere with evaluation
of study treatment or interpretation of patient safety or study results, or inability
to comply with the study and follow-up procedures.


17. Participation in another clinical study with investigational medicinal products within
4 weeks before the first study drug administration.


18. Clinically active infections within 2 weeks before the first study drug
administration.


19. Treatment with therapeutic oral or i.v. antibiotics within 2 weeks before the first
study drug administration. Patients receiving prophylactic antibiotics (e.g. for
prevention of a urinary tract infection or to prevent chronic obstructive pulmonary
disease exacerbation) are eligible.


20. Known hypersensitivity to any of the study drugs, study drug classes, or excipients in
the formulation.


21. Current diagnosis of any retinal disorders including retinal detachment, retinal
pigment epithelial detachment (RPED), serous retinopathy or retinal vein occlusion or
risk factors for RVO (e.g., uncontrolled glaucoma or history of hyperviscosity or
hypercoagulability syndrome).


22. Peripheral sensory neuropathy of CTCAE v.5.0 Grade 2 or higher


23. Major surgery, open biopsy or significant traumatic injury within 4 weeks before the
first study drug administration (central line surgery is not considered major
surgery).


24. Renal failure requiring peritoneal dialysis or hemodialysis.


25. Substance abuse, medical, psychological or social conditions that may interfere with
the patient's participation in the study or evaluation of the study results.

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Advanced Information
Descriptive Information
Brief Title  ICMJE Palbociclib and Binimetinib in Advanced Triple Negative Breast Cancer
Official Title  ICMJE Phase IB Clinical Trial of Palbociclib and Binimetinib in Advanced Triple Negative Breast Cancer With Hyperactivation of ERK and/or CDK4/6
Brief Summary This study is an interventional, prospective, multicentric, single-arm, open label, phase IB clinical trial. This study will be carried out in Patients diagnosed of metastatic or locally advanced unresectable triple negative breast cancer with activation of ERK and/or CDK4/6 in which the following will be assesed: the overall response rate, the aggregation of antitumor effect depending on the different kinome profiles and the safety profile to the combination of Palbociclib and Binimetinib.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:
Prospective, multicentric, single-arm, open label, phase IB clinical trial.
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Triple Negative Breast Cancer
Intervention  ICMJE Drug: Combination, Palbociclib + Binimetinib

Patients will then start treatment with continuous oral binimetinib 45 mg/BID and palbociclib 100 mg daily, 21 days on / 7 days off, until disease progression. Study treatment will continue until disease progression.

If treatment tolerance is good, after a full cycle patients will be allowed to escalate palbociclib to 125, according to the study investigators' decision. Alternatively, patients with nontolerable grade 2 events will resume at 30 mg/BID of binimetinib upon recovery, maintaining palbociclib at 100 mg 21-on/7-off. Depending on the side-effects, in case of clear relationship with palbociclib is established, palbociclib -instead of binimetinib - will be reduced to 75 mg daily.

Study Arms  ICMJE Experimental: Palbociclib + Binimetinib
Intervention: Drug: Combination, Palbociclib + Binimetinib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: July 28, 2020)
28
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 1, 2023
Estimated Primary Completion Date June 1, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Women >18 years-old.
  2. Diagnostic of metastatic or locally advanced non-resectable TNBC.
  3. Patient that have received up to two previous lines of therapy for metastatic TNBC and failed to last treatment. Previous treatments can be of any nature (chemotherapy, immunotherapy, antiangiogenics, experimental therapy, etc.).
  4. Availability of tumor tissue for ERK and CDK4/6 testing is mandatory prior to study inclusion, preferably obtained after last treatment or the most recent sample as possible (from metastatic site or first diagnosis according to sample availability). If the patient has not a tumor sample available prior to study inclusion, the patient will not be allowed to participate in the study.
  5. Ability to understand and signing of the written patient information/informed consent form (PIS/ICF) for ERK and CDK4/6 testing. ERK and CDK4/6 testing will be performed centrally at CNIO.
  6. Ability to understand and signing the written PIS/ICF for study treatment eligibility. Signed informed consent form must be available before any studyspecific procedure for the respective study parts may begin.
  7. Positivity for ERK and/or CDK4/6, defined as showing an H-score above the top-quartile according to published definitions [1].
  8. ECOG performance status of 0-1.
  9. Evaluable disease according to RECIST 1.1 criteria.
  10. Life expectancy >24 weeks.
  11. Adequate bone marrow, liver and renal function as assessed by laboratory requirements conducted within 7 days before first study drug administration:

    1. Absolute neutrophil count (ANC) ? 1.500/mm3 (without granulocyte colony-stimulating factor support within 2 weeks before the first study drug administration)
    2. Hemoglobin ? 9 g/dL (without transfusion or erythropoietin within 4 weeks before the first study drug administration)
    3. Platelet count ? 100.000/mm3 (without transfusion within 2 weeks before the first study drug administration)
    4. Total bilirubin ? 2 X the upper limit of normal (ULN).
    5. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ? 2.5 X ULN (? 5 times ULN for patients with liver metastases)
    6. Glomerular filtration rate (GFR) > 50 mL/min/1.73 m2 according to the modification of diet in renal disease (MDRD) abbreviated formula.
  12. Patients must have recovered to ? Grade 1 in terms of toxicity from prior treatments (excluding neuropathy which can be ? Grade 2, and alopecia).
  13. Patients must be able to take oral medications.
  14. Patients must have adequate cardiac function, defined as:

    1. Left ventricular ejection fraction (LVEF) > 50% as determined by echocardiogram or multigated acquisition scan (MUGA).
    2. QTc < 480 msec.
  15. Negative serum pregnancy test in women of childbearing potential (performed within 7 days before the first treatment). Negative results must be available before the first study drug administration.
  16. Women of reproductive potential must agree to use adequate contraception when sexually active. This applies for the time period since the signature of the informed consent form and until at least 1 month after the last study drug administration. The definition of adequate contraception will be based on the judgment of the investigator and on local requirements. Acceptable methods of contraception include, but are not limited to, (i) condoms (male or female) with or without a spermicidal agent; (ii) diaphragm or cervical cap with spermicide; (iii) intra-uterine device; (iv) hormone-based contraception.Zoledronic acid or denosumab started prior to trial registration is allowed, but in case they are required after initiation of trial procedures, adequate justification is required.

Exclusion Criteria:

  1. Participants who have had chemotherapy, radiotherapy, or major surgery within 2 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study.
  2. Patients that received during the metastatic disease setting any of the study drugs, palbociclib or binimetinib.
  3. Participants receiving any other study agents concurrently with the study drugs. Zoledronic acid or denosumab for bone metastases, started at least 15 days prior to enrollment are allowed.
  4. Participants with symptomatic brain metastases that require chronic steroids. Patients with a history of brain metastases are permitted to enroll as long as they have been treated, are off of steroids, and have been stable for a minimum of one month on imaging.
  5. Irradiation of single lesions in the last 28 days prior to trial recruitment, if it is the only location of the disease and it has not progressed. Patients with radiated single lesions that has progressed are allowed.
  6. Concurrent use of strong CYP3A4 inhibitors/inducers is prohibited due to drug-drug interactions with palbociclib. Moderate CYP3A4 inhibitors/inducers should be used with caution.
  7. Uncontrolled intercurrent illness including, but not limited to:

    1. ongoing or active infection requiring systemic treatment
    2. symptomatic congestive heart failure
    3. cardiac arrhythmia
    4. psychiatric illness/social situations that would limit compliance with study requirements
    5. hypertension, defined as systolic blood pressure > 160 mmHg despite medical management
    6. myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting < 6 months prior to screening
  8. History of QT syndrome, Brugada syndrome, known history of QTc prolongation, or Torsades de Pointes.
  9. History of Gilbert's syndrome.
  10. History of neuromuscular disorders that are associated with elevated CK (e.g. inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy).
  11. Previous or concurrent cancer except:

    1. cervical carcinoma in situ
    2. treated basal-cell carcinoma or squamous cell skin cancer c. any other cancer curatively treated > 3 years before the first study drug administration
  12. Malabsorption syndrome or uncontrolled nausea, vomiting, or diarrhea that may interfere with the absorption of oral study medication in the opinion of the investigator.
  13. Pregnant women or breast-feeding.
  14. Known HIV-positive individuals on combination antiretroviral therapy.
  15. Active hepatitis B virus (HBV; chronic or acute; defined as having a known positive hepatitis B surface antigen [HBsAg] test at the time of screening) or hepatitis C infection requiring treatment.

    1. Patients with past HBV infection or resolved HBV infection (defined as the presence of hepatitis B core antibody [HBcAb] and absence of HBsAg) are eligible if HBV DNA is negative.
    2. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
  16. Any condition that in the opinion of the investigator would interfere with evaluation of study treatment or interpretation of patient safety or study results, or inability to comply with the study and follow-up procedures.
  17. Participation in another clinical study with investigational medicinal products within 4 weeks before the first study drug administration.
  18. Clinically active infections within 2 weeks before the first study drug administration.
  19. Treatment with therapeutic oral or i.v. antibiotics within 2 weeks before the first study drug administration. Patients receiving prophylactic antibiotics (e.g. for prevention of a urinary tract infection or to prevent chronic obstructive pulmonary disease exacerbation) are eligible.
  20. Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation.
  21. Current diagnosis of any retinal disorders including retinal detachment, retinal pigment epithelial detachment (RPED), serous retinopathy or retinal vein occlusion or risk factors for RVO (e.g., uncontrolled glaucoma or history of hyperviscosity or hypercoagulability syndrome).
  22. Peripheral sensory neuropathy of CTCAE v.5.0 Grade 2 or higher
  23. Major surgery, open biopsy or significant traumatic injury within 4 weeks before the first study drug administration (central line surgery is not considered major surgery).
  24. Renal failure requiring peritoneal dialysis or hemodialysis.
  25. Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results.
Sex/Gender  ICMJE
Sexes Eligible for Study:Female
Gender Based Eligibility:Yes
Gender Eligibility Description:In this Case, gender is a eligibility criteria because it is a specific cancer in women.
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Miguel Ángel Quintela-Fandino, MD+34917328000[email protected]
Listed Location Countries  ICMJE Spain
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04494958
Other Study ID Numbers  ICMJE PALBOBIN
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Fundacion Oncosur
Study Sponsor  ICMJE Fundacion Oncosur
Collaborators  ICMJE
  • Pfizer
  • Apices Soluciones S.L.
  • Pierre Fabre Ibérica, S.A.
Investigators  ICMJE
Principal Investigator:Miguel Ángel Quintela-Fandino, MDCentro Nacional de Investigaciones Oncológicas
PRS Account Fundacion Oncosur
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP