Phase II Study of Ilorasertib (ABT348) in Patients With CDKN2A Deficient Solid Tumors

Study Overview
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Brief Summary
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The goal of this clinical research study is to learn if ilorasertib (ABT-348) can help to control CDKN2A-deficient cancer. CDKN2A deficiency is a type of mutation (a genetic change). The safety of this drug will also be studied.

Detailed Description
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Study Drug Administration: Each study cycle is 28 days. You will take ABT-348 by mouth 2 times each day on Days 1, 8, and 15 of each cycle. The first dose you take on these days is called Dose 1, and the second dose you take each day is called Dose 2. You will take Dose 1 (the earlier dose) of ABT-348 with 4 ounces (about ½ cup) of water. You should fast (not eat or drink anything except water) for 8 hours before taking this dose. You need to fast before this dose because eating food may affect the levels of the study drug that is able to enter your system. You will be allowed to have a light snack 2 hours after Dose 1, and then you may eat anything you like 4 hours after the dose. You should take Dose 2 (the later dose) as close as possible to 6 hours after the first dose, but not less than 6 hours after the first dose. You do not need to fast before Dose 2. You may eat and drink normally around this dose. Study Visits: On Day 1 of each cycle, and on Days 8 and 15 of Cycles 1 and 2: You will have a physical exam. Blood (about 2 teaspoons) will be drawn for routine tests. You will have an EKG (Day 1 of Cycle 2 only). For Cycle 3 and after, you will have these EKGs repeated every 3 cycles (Cycles 6, 9, 12, and so on). On Day 1 of all cycles, urine will be collected for routine tests. On Day 1 of Cycles 2 and beyond, if you can become pregnant, blood (about 1 teaspoon) or urine will be collected for a pregnancy test. Every 8 weeks, you will have a chest x-ray, bone scan, MRI/CT or PET/CT to check the status of the disease. You may be able to have some of these tests/procedures performed at a local lab, clinic, or doctor's office that is closer to your home. The results of these tests will be sent to the study doctor for review. The study doctor or research staff will discuss this option with you in more detail. Length of Study Drug Administration: You may continue taking the study drug for as long as the doctor thinks it is in your best interest. You will no longer be able to take the study drug if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions. You participation on this study will be over after your last dose of study drug. This is an investigational study. ABT-348 is not FDA approved or commercially available. It is currently being used for research purposes only. The study doctor can explain how the study drug is designed to work. Up to 65 participants will be enrolled in this study. All will take part at MD Anderson.

Official Title
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A Proof-of-Concept Study for Ilorasertib (ABT-348) Activity in Patients With CDKN2A-Deficient Advanced Solid Cancers: a Phase II Basket Trial

Conditions
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Advanced Cancers

Intervention / Treatment
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* Drug: Ilorasertib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with histologically confirmed, advanced or metastatic cancer for which standard curative or palliative measures do not exist or are no longer effective. Patients must have CDKN2A-deficient tumor (deletion or mutation). Definition of CDKN2A deficient tumor: #1. CDKN2A deletion or mutation by any CLIA-certified sequencing OR #2. >/= 30% of tumor cells with (at least) hemizygous deletion by FISH. Status will be determined from archived tissue. Patients must have measurable disease by RECIST 1.1. Patients must be >/=18 years of age. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2. Subject has adequate renal function as demonstrated by serum creatinine value of </= 1.5 times the upper limit of normal (ULN) and either an estimated creatinine clearance value of >/= 50 mL/min as determined by the Cockcroft-Gault formula or a creatinine clearance value of >/= 50 mL/min based on a 24 hour urine collection. Subject has adequate liver function as demonstrated by serum bilirubin </= 2 x ULN and AST and ALT </= 2.5 x ULN. For subjects with liver metastasis, adequate liver function is demonstrated by serum bilirubin </= 2 x ULN and AST/ALT </= 5.0 x ULN. Subject has adequate bone marrow as demonstrated by absolute neutrophil count (ANC) >/= 1,500/mm3 (1.5 x 10^9/L); Platelets >/= 100,000/mm2 (100 x 10^9/L); Hemoglobin >/= 9.0 g/dL (1.4 mmol/L). Subject has QTc interval < 500 msec on baseline electrocardiogram. The subject has a documented Left Ventricular Ejection Fraction > 50%. Women of child-bearing potential and men must agree to use adequate contraception (one of the following listed below) prior to the study entry, for the duration of study participation and up to 3 months following completion of therapy. Women of child-bearing potential must have a negative pregnancy test within 7 days prior to initiation of treatment and/or post menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential. -Total abstinence from sexual intercourse (minimum one complete menstrual cycle) -Vasectomized male subjects or vasectomized partner of female subjects -Intrauterine device -Double-barrier method (condoms, contraceptive sponge, diaphragm or vaginal ring with spermicidal jellies or cream) -Additionally, male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must agree to use condoms for the duration of the study and for 3 months following completion of therapy. Ability to understand and willingness to sign informed consent form prior to initiation of the study and any study procedures. Signed informed consent approved by the Institutional Review Board prior to patient entry Exclusion Criteria: Patients with CDKN2A wild type by a CLIA-certified laboratory Subject has known active CNS involvement. The subject has untreated brain or meningeal metastases. CT scans are not required to rule out brain or meningeal metastases unless there is a clinical suspicion of central nervous system disease. Subjects with treated brain metastases that are radiographically or clinically stable for at least 4 weeks after therapy and have no evidence of cavitation or hemorrhage in the brain lesion(s) are eligible, providing that they are asymptomatic, and do not require corticosteroids (must have discontinued steroids at least 1 week prior to study drug administration). Subject has received anti-cancer therapy including chemotherapy, immunotherapy, radiotherapy, hormonal, biologic or any investigational therapy within a period of 21 days or 5 half-lives (whichever is shorter) prior to Study Day 1. Subject has unresolved toxicities from prior anti-cancer therapy, defined as any Common Terminology Criteria for Adverse Events (NCI CTCAE v 4.0) grade 2 or higher clinically significant toxicity (excluding alopecia). Subject has had major surgery within 28 days prior to Study Day 1. Subject currently exhibits symptomatic or persistent, uncontrolled hypertension defined as diastolic blood pressure > 90 mmHg or systolic blood pressure > 140 mmHg. Subjects may be re-screened if blood pressure is shown to be controlled with or without intervention. Subject has proteinuria defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v 4.0) grade > 1 at baseline as measured by a urine dipstick (2+ or greater) and confirmed by a 24 hour urine collection (>/= 1 g/24 hrs). Subjects may be re-screened if proteinuria is shown to be controlled with or without intervention. Subject is receiving therapeutic anticoagulation therapy. Low dose anti-coagulation (e.g., low dose heparin or warfarin) for catheter prophylaxis will be permitted. Use of Aspirin for treatment of Atrial Fibrillation will also be permitted. Patients with another primary malignancy within 3 years prior to starting study treatment with the exception of adequately treated basal cell carcinoma, squamous cell carcinoma or other non-melanomatous skin cancer, or in-situ carcinoma of the uterine cervix. Clinically significant uncontrolled condition(s) including but not limited to: Active uncontrolled infection, Symptomatic congestive heart failure, Unstable angina pectoris or cardiac arrhythmia (subjects with stable atrial fibrillation are not excluded), History of adrenal insufficiency. Psychiatric illness/social situation that would limit compliance with study requirements. Subject has a known infection with HIV, Hepatitis B or Hepatitis C. Subject is known to have poorly controlled diabetes mellitus defined as HbA1c > 7%; subjects with a history of transient glucose intolerance due to corticosteroid administration are allowed in this study if all other inclusion/exclusion criteria are met. Any medical condition which in the opinion of the study investigator places the subject at an unacceptably high risk for toxicities. Subject is unable to swallow or absorb oral tablets normally Female subject who is lactating or pregnant. Subject takes CYP3A Inhibitors/Inducers within 7 days prior to the study drug administration.

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: Ilorasertib (ABT-348)<br>Part 1 Dose of Ilorasertib: 200 mg administered by mouth twice daily on Days 1, 8, and 15 of each 28-day cycle. Part 2 Expansion: Ilorasertib200 mg administered by mouth twice daily on Days 1, 8, and 15 of each 28-day cycle. | Drug: Ilorasertib<br>* 200 mg administered by mouth twice daily on Days 1, 8, and 15 of each 28-day cycle.<br>* Other names: ABT-348;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate | Partial or complete response to ilorasertib | through study completion, maximum 18 months | 
| Efficacy Signal | Selection of specific tumor type where the drug is potentially active for recruitment of additional patients (expansion) | through study completion, maximum 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability | Safety and tolerability of ilorasertib. | through study completion, maximum 18 months' | 
| Pharmacodynamic Activity | Assessment of the pharmacodynamic effects of ilorasertib by immunohistochemistry for phospho-histone H3 | Cycle 1 Day 1 at up to 72 hours prior to the first dose and 2-4 hours after the second dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ilorasertib, Advanced or metastatic cancer., Advanced Cancers, CDKN2A-Deficient Advanced Solid Cancers, ABT-348