Phase II Study of Ilorasertib (ABT348) in Patients With CDKN2A Deficient Solid Tumors
Condition: Advanced Cancers
Intervention: Ilorasertib
Intervention description: 200 mg administered by mouth twice daily on Days 1, 8, and 15 of each 28-day cycle.
Intervention MeSH terms: Ilorasertib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 12.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Advanced Cancers; CDKN2A-Deficient Advanced Solid Cancers; Advanced or metastatic cancer.; Ilorasertib; ABT-348

Summary:

      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.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Patients with histologically confirmed, advanced or metastatic cancer for which
             standard curative or palliative measures do not exist or are no longer effective.

          2. 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.

          3. Patients must have measurable disease by RECIST 1.1.

          4. Patients must be >/=18 years of age.

          5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2.

          6. 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.

          7. 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.

          8. 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).

          9. Subject has QTc interval < 500 msec on baseline electrocardiogram.

         10. The subject has a documented Left Ventricular Ejection Fraction > 50%.

         11. 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.

         12. Ability to understand and willingness to sign informed consent form prior to
             initiation of the study and any study procedures.

         13. Signed informed consent approved by the Institutional Review Board prior to patient
             entry

        Exclusion Criteria:

          1. Patients with CDKN2A wild type by a CLIA-certified laboratory

          2. 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).

          3. 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.

          4. 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).

          5. Subject has had major surgery within 28 days prior to Study Day 1.

          6. 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.

          7. 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.

          8. 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.

          9. 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.

         10. 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.

         11. Psychiatric illness/social situation that would limit compliance with study
             requirements.

         12. Subject has a known infection with HIV, Hepatitis B or Hepatitis C.

         13. 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.

         14. Any medical condition which in the opinion of the study investigator places the
             subject at an unacceptably high risk for toxicities.

         15. Subject is unable to swallow or absorb oral tablets normally

         16. Female subject who is lactating or pregnant.

         17. Subject takes CYP3A Inhibitors/Inducers within 7 days prior to the study drug
             administration.