Abemaciclib for Patients With Retinoblastoma-Positive, Triple Negative Metastatic Breast Cancer

• ClinicalTrials.gov Identifier: NCT03130439
• Recruitment Status: Terminated
• First Posted: April 26, 2017
• Results First Posted: September 22, 2022
• Last Update Posted: September 28, 2023
• Sponsor: Dana-Farber Cancer Institute
• Collaborator: Eli Lilly and Company
• Information provided by (Responsible Party): Sara Tolaney, MD, Dana-Farber Cancer Institute

Study Description

Brief Summary:

This research study is studying a drug called Abemaciclib as a possible treatment for have metastatic triple-negative type of breast cancer.

Condition or disease	Intervention/treatment	Phase
Breast Cancer	Drug: Abemaciclib	Phase 2

Detailed Description:

This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. "Investigational" means that the intervention is being studied.

The FDA (the U.S. Food and Drug Administration) has not approved abemaciclib as a treatment for any disease.

Some triple-negative breast cancers show expression of the Rb protein and are referred to as "Rb-positive." The Rb protein is important because it controls the way that cancer cells divide and grow. Drugs like abemaciclib work by changing the way that Rb functions. This can potentially stop cancer cells from dividing, and can also potentially lead to cancer cell death.

In this research study, the investigators are are looking to see how safe abemaciclib is and how well it will work to help people with triple-negative breast cancer that is Rb-positive.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 27 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Study of Abemaciclib for Patients With Retinoblastoma-Positive, Triple Negative Metastatic Breast Cancer
• Actual Study Start Date: May 26, 2017
• Actual Primary Completion Date: August 18, 2021
• Actual Study Completion Date: January 30, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Abemaciclib; -Abemaciclib will be administered orally, twice daily on days 1 to 28	Drug: Abemaciclib; Abemaciclib (LY2835219) has been shown in vitro to be a selective ATP-competitive inhibitor of CDK4 and CDK6 kinase activity that prevents the phosphorylation and subsequent inactivation of the Rb tumor suppressor protein, thereby inducing G1 cell cycle arrest and inhibition of cell proliferation.; Other Name: LY2835219

Outcome Measures

Primary Outcome Measures :

1. Objective Response Rate [ Time Frame: 2 years ]
   Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR; Overall Response Rate(ORR) = (CR + PR)/sample size.

Secondary Outcome Measures :

1. Progression Free Survival [ Time Frame: Baseline to the earlier of progression (per Response Evaluation Criteria in Solid Tumors 1.1), date of death due to any cause, or date of last disease evaluation. Participants will be followed up up to 16.5 months. ]

   Progression-Free Survival (PFS) is defined as the time from randomization (or registration) to the earlier of progression (per Response Evaluation Criteria in Solid Tumors 1.1) or death due to any cause. Participants alive without disease progression are censored at date of last disease evaluation.

   Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

2. Overall Survival [ Time Frame: Baseline to date of death due to any cause, or at date last known alive.Participants will be followed once every 6 months until death.Those removed from protocol therapy for unacceptable adverse event(s) will be followed until resolution or stabilization. ]
   Overall Survival (OS) is defined as the time from randomization (or registration) to death due to any cause, or censored at date last known alive.
3. Disease Control Rate [ Time Frame: 2 years ]
   Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), Neither sufficient shrinkage (compared to baseline) to qualify for partial or complete response (CR or PR) nor sufficient increase (taking as reference the smallest sum of diameters at baseline or while on study, whichever is smallest) to qualify for progressive disease (PD); Disease control rate is defined as CR + PR + SD ≥ 16weeks
4. Clinical Benefit Rate [ Time Frame: 2 years ]
   Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), Neither sufficient shrinkage (compared to baseline) to qualify for partial or complete response (CR or PR) nor sufficient increase (taking as reference the smallest sum of diameters at baseline or while on study, whichever is smallest) to qualify for progressive disease (PD); Clinical benefit rate is defined as CR+PR+SD ≥ 24weeks

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed invasive breast cancer, which is recurrent, locally advanced, unresectable or metastatic.
• Patients must have at least one lesion that is not within a previously radiated field and that is measurable on computerized tomography (CT) or magnetic resonance imaging (MRI) scans per RECIST version 1.1. Bone lesions are not considered measurable.

• Either the primary tumor and/or metastatic tumor must be triple-negative on the most recent sample as defined below:

  • Hormone receptor status: the invasive tumor must be ER- and PR-negative, or staining present in <1% by immunohistochemistry (IHC)
  • HER2 status: the invasive tumor must be Human Epidermal Growth Factor Receptor 2 Negative (HER2-negative) by the ASCO CAP guidelines

• Either the primary tumor and/or the metastatic tumor must be RB positive as defined below:

  --RB status: the invasive tumor must have greater than 50% of tumor cells staining positive for RB.

• Prior Chemotherapy:

  • Patients may have received 1-3 prior systemic therapies for metastatic disease (note: for patients who have first developed recurrent/metastatic disease within 12 months of completing any (neo)-adjuvant therapy for triple-negative breast cancer, the (neo)-adjuvant therapy is counted as a prior line of therapy).
  • Patients must have been off treatment with myelosuppressive chemotherapy for at least 21 days or nonmyelosuppressive agents for 14 days before registration. Patients should also be adequately recovered (to baseline or grade 1) from acute toxicities of prior treatment except for residual alopecia and peripheral neuropathy.
• Prior biologic therapy: Patients must have discontinued all biologic therapy at least 21 days before registration.
• Prior radiation therapy: Patients may have received prior radiation therapy in either the metastatic or early-stage setting. Radiation therapy must be completed at least 14 days prior to study registration.
• Patients on bisphosphonates or RANK-L inhibitors may continue receiving these therapies during study treatment. There is no washout period required between the last dose of these therapies and the start of abemaciclib.
• The patient has an Eastern Cooperative Oncology Group (ECOG) performance status 0-1

• Patients must have normal organ and marrow function as defined below:

  • Absolute neutrophil count ≥1500/mm3
  • Platelets ≥100,000/mm3
  • Hemoglobin ≥8 g/dL
  • Total Bilirubin ≤1.5x the upper limit of normal (ULN)
  • Serum creatinine ≤1.5 mg/dL OR calculated GFR ≥60mL/min
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 times the upper limit of normal. For patients with documented liver metastases, AST/ALT ≤ 5.0 times the upper limit of normal.
• Female subjects of childbearing potential must have a negative serum pregnancy test at screening. Women of childbearing potential are defined as those who have not been surgically sterilized and have had a menstrual period in the past year
• The patient must be ≥18 years old
• Capable of understanding and complying with the protocol and has signed the informed consent document.
• Able to swallow study drug.
• Sexually active patients (male and female) must use medically acceptable methods of contraception during the course of the study and for 3 months after completion of study treatment. If a woman becomes pregnant or suspects she is pregnant while participating in this study, she should inform her treating physician immediately. While on the study and for 3 months after final drug administration, women may not breast-feed.
• Confirmed availability of formalin-fixed, paraffin-embedded (FFPE) tumor tissue
• Patients with tumor that is felt to be accessible to biopsy must be willing to provide tissue from a newly obtained core biopsy of a tumor lesion at baseline. Biopsies will be obtained up to 1 week (7 days) prior to initiation of treatment on Cycle 1, Day 1. Patients who undergo an attempted research biopsy procedure for the purpose of this protocol, and in whom inadequate tissue is obtained, are not required to undergo a repeat biopsy in order to continue on protocol.

Exclusion Criteria:

• Received a prior CDK4/6 inhibitor.
• Undergone major surgery within 14 days of the initial dose of study drug
• Received another investigational agent (defined as any agent/device that has not received regulatory approval for any indication) within 14 days of the first dose of study drug for a nonmyelosupressive agent, or 21 days of the first dose of study drug for a myelosuppressive agent.
• Has any severe concurrent disease, infection, or comorbid condition that renders the patient inappropriate for enrollment in the opinion of the investigator.
• Has an active bacterial, fungal, and/or known viral infection. Patients with known HIV infection are excluded given the potential for interactions between antiretroviral agents and abemaciclib, and the potential for increased risk of life-threatening infection with therapy that is myelosuppressive. Patients with known Hepatitis B or Hepatitis C infection are excluded only if there is evidence of active infection (detectable Hepatitis B surface antigen, detectable Hepatitis C RNA)

• Documented brain metastases that are untreated, symptomatic, or require therapy to control symptoms. Participants with previously diagnosed brain metastases are eligible if they have completed treatment at least one month prior to trial registration, are neurologically stable, and have recovered from effects of radiotherapy or surgery.

  • Any corticosteroid use for brain metastases must have been discontinued without the subsequent appearance of symptoms for ≥2 weeks before the first study drug.
  • Treatment for brain metastases may have included whole brain radiotherapy, radiosurgery, or a combination as was deemed appropriate by the treating physician.
  • Patients who meet the above criteria and are clinically stable on anti-convulsant medication are eligible only if their anti-convulsant does not alter hepatic cytochrome P450 activity in a way that might interfere with metabolism of abemaciclib.
• Pregnant women are excluded from this study because of the potential for teratogenic effects.
• Lactating women are excluding from the study.
• Individuals with a history of a second malignancy are ineligible except for the following circumstances: individuals with a history of other malignancies are eligible if they have been disease-free for at least 5 years and are deemed by the investigator to be at low risk for recurrence of that malignancy. Individuals with the following cancers are eligible if they are diagnosed and have completed treatment within the past 5 years: cervical cancer in situ, and non-melanoma cancer of the skin. Patients with other cancers diagnosed within the past 5 years and felt to be at low risk of recurrence should be discussed with the principle investigator to determine eligibility.
• Have received any live vaccination within 28 days of first dose of study drug.

Contacts and Locations

Locations

United States, Massachusetts

Dana-Farber Cancer Institute

Boston, Massachusetts, United States, 02115

Sponsors and Collaborators

Dana-Farber Cancer Institute

Eli Lilly and Company

Investigators

• Principal Investigator: Sara Tolaney, MD, MPH; Dana-Farber Cancer Institute

  Study Documents (Full-Text)

Documents provided by Sara Tolaney, MD, Dana-Farber Cancer Institute:

Study Protocol and Statistical Analysis Plan  [PDF] November 11, 2019

More Information

• Responsible Party: Sara Tolaney, MD, Principal Investigator, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT03130439
• Other Study ID Numbers: 17-024
• First Posted: April 26, 2017
• Results First Posted: September 22, 2022
• Last Update Posted: September 28, 2023
• Last Verified: September 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Sara Tolaney, MD, Dana-Farber Cancer Institute:

Breast Cancer

Additional relevant MeSH terms:

Breast Neoplasms; Retinoblastoma; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Retinal Neoplasms; Eye Neoplasms; Eye Diseases, Hereditary; Eye Diseases; Retinal Diseases