Palbociclib In Progressive Brain Metastases

Study Overview
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Brief Summary
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This research study is studying palbociclib as a possible treatment for recurrent brain metastases. - Pfizer, a pharmaceutical company, is supporting this research study by providing the study drug as well as funding for research activities

Detailed Description
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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. This is a study designed to evaluate the efficacy and safety of palbociclib in recurrent brain metastases. Palbociclib is being studied for use in the treatment of a broad range of cancers. This type of drug inhibits cell growth in the cells called cyclin-dependent kinases which promote tumor cell proliferation. The FDA (the U.S. Food and Drug Administration) has not approved palbociclib for participants specific disease but it has been approved for other uses

Official Title
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A Phase 2 Study of Palbociclib in Progressive Brain Metastases Harboring Alterations in the CDK Pathway

Conditions
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Metastatic Malignant Neoplasm to Brain

Intervention / Treatment
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* Drug: Palbociclib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must have histologically or cytologically confirmed disease from any solid tumor Participants must have measurable disease in the CNS, defined as at least one lesion that can be accurately measured in at least one dimension as ≥10 mm . Participants must have progressive CNS lesions, as defined by one of the following: Patients may have multiple progressive CNS lesions, some of which have been treated by SRS or surgery. Patients are eligible if they have one or more un-treated (by surgery or SRS) progressive lesions that is measurable. Patients have measurable residual or progressive lesions after surgery. Patients who have had prior WBRT and/or SRS are eligible but there needs to be unequivocal evidence of progression of at least one lesion treated by radiation (e.g. tissue diagnosis). Biopsy can be considered for definitive diagnosis. Patients who have previously been treated with systemic therapy for CNS metastases are eligible. Age ≥ 18 years. The toxicity of palbociclib in children is unknown. ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A) Participants must have normal organ and marrow function as defined below: leukocytes ≥3,000/mcL absolute neutrophil count ≥1,500/mcL platelets ≥100,000/mcL hemoglobin >9g/dL total bilirubin ≤ 1.5 x institutional upper limit of normal --- OR > 1.5 x institutional upper limit of normal allowed if direct bilirubin is within normal range. AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal creatinine within normal institutional limits --- OR creatinine clearance ≥60 mL/min/1.73 m2 for participants with creatinine levels above institutional normal. baseline QTc <480ms The effects of palbociclib on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 6 months after completion of palbociclib administration. Ability to understand and the willingness to sign a written informed consent document. Tissue from a prior craniotomy or biopsy for genetic sequencing (at least one FFPE block or 15 unstained slides). Patients previously assessed for genetic sequencing who meet requirements of section 9.2.1 do not need to have additional tissue available for prospective genetic sequencing. Presence of alteration in CDK pathway (amplifications in CDK4, CDK6, CCND1, CCND2, CCND3 or CCNE1 or loss of CDKN2A) Patients with progressive extracranial disease will not be excluded. Stable corticosteroids for at least 7 days Exclusion Criteria: Prior treatment with CDK4/6 inhibitor Participants who have had chemotherapy, immunotherapy or radiotherapy within 2 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 2 weeks earlier. Participants who are receiving any other investigational agents Participants who are receiving other concurrent chemotherapies or immunotherapies for their cancer (except for patients who will receive letrozole, anastrozole, exemestane, tamoxifen, fulvestrant, trastuzumab, bisphosphonates, or ovarian suppression therapy) Leptomeningeal involvement of cancer History of allergic reactions attributed to compounds of similar chemical or biologic composition to palbociclib (including abemaciclib) Participants receiving any medications or substances that are moderate or strong inhibitors or inducers of CYP3A isoenzymes are ineligible. Lists including medications and substances known or with the potential to interact with the CYP3A isoenzymes are provided in Appendix C, and can also be found within section 5.4. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such as the Physicians' Desk Reference may also provide this information. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Pregnant women are excluded from this study because the effect of palbociclib on a developing fetus is unknown. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with palbociclib, breastfeeding should be discontinued if the mother is treated with palbociclib. HIV-positive participants on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with palbociclib. In addition, these participants are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in participants receiving combination antiretroviral therapy when indicated. Current use of drugs that are known to prolong the QT interval (See Appendix C) Unable to undergo MRI scans. QTc>480 msec (based on the mean value of the triplicate ECGs), family or personal history of long or short QTc prolongation, or Torsade de Pointes (TdP). Uncontrolled electrolyte disorders that can compound the effects of QTc-prolonging drug (eg. hypocalcemia, hypokalemia, hypomagnesemia

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Palbociclib<br>Description Patients who fulfill eligibility criteria will be entered into the trial to receive Palbociclib After the screening procedures confirm participation in the research study: Palbociclib- Fixed Dose, daily for 21 days per cycle. The participant will be requested to maintain a medication diary of each dose of medication. The medication diary will be returned to clinic staff at the end of each cycle. | Drug: Palbociclib<br>* 125 mg by mouth daily<br>* Other names: Ibrance;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Benefit Rate (Intracranial) | Simon two-stage design comparing the proportion of intracranial responders (as defined by CR, PR or SD) under a null hypothesis response rate of 10% against an alternative of 30%. | 8 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Benefit Rate (Extracranial) | RECIST (CR, PR, SD) | 8 Weeks | 
| Intracranial disease progression rate |  | Time from registration to the earlier of progression or death due to any cause. Patients will be followed for a maximum of 2 years after End-of-Treatment visit. | 
| Extracranial disease progression rate |  | Time from registration to the earlier of progression or death due to any cause. Patients will be followed for a maximum of 2 years after End-of-Treatment visit. | 
| Overall Survival Rate | Kaplan-Meier estimates of overall survival will be presented with 90% confidence intervals estimated using log(-log(survival)) methodology | registration to death due to any cause, or censored at date last known alive. Patients will be followed for a maximum of 2 years after End-of-Treatment visit. | 
| Number of Participants with Grade 3 or more hematologic toxicity; grade 3 or more neurologic toxicity |  | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Recurrent Brain metastases