Summary

This phase I trial studies the side effects and best dose of abemaciclib when given together with radiation therapy in treating younger patients with newly diagnosed diffuse intrinsic pontine glioma (a type of central nervous system tumor that forms from glial [supportive] tissue of the brain and spinal cord), or solid tumors that have come back (recurrent) or does not respond to treatment (refractory), or malignant brain tumors. Abemaciclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving abemaciclib together with radiation therapy may be a better treatment in patients with diffuse intrinsic pontine glioma, solid tumors, or malignant brain tumors.

Objectives

PRIMARY OBJECTIVES:
I. To estimate the maximum tolerated dose (MTD) of abemaciclib (LY2835219) administered concurrently with radiation therapy (RT) in pediatric research participants with newly diagnosed diffuse intrinsic pontine glioma (DIPG).
II. To estimate the MTD of abemaciclib (LY2835219) in children and young adults with recurrent/refractory solid tumors, including malignant tumors of the brain and spine (World Health Organization [WHO] grade III/IV).
III. To characterize the pharmacokinetics of abemaciclib (LY2835219) in pediatric patients and relate drug exposure to toxicity.

SECONDARY OBJECTIVES:
I. To characterize toxicities and/or adverse events associated with the chronic use of abemaciclib (LY2835219).
II. To evaluate changes in phosphorylation of histone H3, retinoblastoma (Rb) and/or topoisomerase (topo)II alpha inhibition in peripheral blood mononuclear cells and investigate the possible relationship between these changes, plasma drug levels of abemaciclib, and outcome measures.
III. To evaluate cyclin-dependent kinase (Cdk)4/6, cyclin D1 (CCND1) and Rb protein and messenger ribonucleic acid (mRNA) expression in tumor tissue where available.
IV. To evaluate the coding transcriptome (RNA sequencing) of tumor tissue where available.
V. To analyze the cargo of protein and mRNA in exosomes in patient plasma as a means of “liquid biopsy” in comparison to primary tumor tissue, as available.
VI. To assess the pattern of failure in newly diagnosed DIPG participants.

OUTLINE: This is a dose escalation study of abemaciclib. Patients are assigned to 1 of 2 treatment strata.

STRATA A NEWLY DIAGNOSED DIPG: Patients receive abemaciclib orally (PO) twice daily (BID) on days 1-28 and undergo 3-dimensional (3-D) conformal radiation therapy once daily (QD) 5 days a week for 6 weeks. Courses with abemaciclib repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity.

STRATA B RECURRENT, REFRACTORY OR PROGRESSIVE SOLID AND MALIGNANT BRAIN TUMORS: Patients receive abemaciclib PO BID on days 1-28. Courses repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 3, 6, 9, 12, 15, 18, 24, 30, and 36 months, and then periodically for 2 years.

Eligibility

1. Patient must have measurable or evaluable disease
2. Body surface area (BSA) >= 0.5 m^2
3. Lansky (for research participants =< 16 years) or Karnofsky (for research participants > 16 years) performance score >= 40 at the time of study enrollment
4. Absolute neutrophil count (ANC) >= 1,000/uL
5. Platelet count >= 75,000/uL (transfusion independent for >= 7 days)
6. Hemoglobin concentration >= 8 g/dL (may be transfused)
7. Patients with bone marrow metastatic disease who do not meet the above criteria will be eligible to enroll in the study with the following count criteria; these patients will not be evaluable for hematologic toxicity or hematologic dose limiting toxicity (DLT) * ANC > 750/uL within 7 days prior to first dose of abemaciclib * Platelet count > 50,000/uL (may receive platelet transfusions) within 7 days prior to first dose of abemaciclib * Hemoglobin >= 7.5 g/dL (may receive red blood cells [RBC] transfusions) within 7 days prior to first dose of abemaciclib
8. Serum creatinine concentration based on age as in the table below or glomerular filtration rate (GFR) > 70 ml/min/1.73 m^2 * =< 5 years, 0.8 mg/dL * 5 < age =< 10 years, 1.0 mg/dL * 10 < age =< 15 years, 1.2 mg/dL * > 15 years, 1.5 mg/dL
9. Total bilirubin concentration =< 1.5 x the institutional upper limit of normal for age
10. Serum glutamate pyruvate transaminase (SGPT) =< 10 x the institutional upper limit of normal for patients on Stratum A; Stratum B patients must have SGPT =< 4 x the institutional upper limit of normal.
11. Adequate cardiac conductivity with corrected QT interval (QTC) of < 450 ms on screening electrocardiogram (ECG)
12. Female research participants of childbearing age must not be pregnant as confirmed by a serum or urine pregnancy test within 1 week of start of treatment; participants must not be breast-feeding
13. All patients should submit an archival tumor biopsy specimen (collected at diagnosis or relapse); patients who have no tumor tissue available may be permitted to participate after discussion with the principal investigator
14. Males or females of reproductive potential may not participate unless they have agreed to use two effective contraceptive methods; abstinence in a non-sexually active child will be sufficient birth control
15. INCLUSION CRITERIA - STRATUM A:
16. Diagnosis of DIPG or high-grade glioma originating from the brain stem
17. Patients have had no previous treatment except corticosteroid use
18. INCLUSION CRITERIA - STRATUM B
19. Patients must have radiologic evidence of recurrent, refractory or progressive malignant central nervous system (WHO grade III or IV) or solid tumor; for patients with radiologic features of DIPG histologic confirmation of diagnosis is not required though biopsy is suggested if clinically indicated
20. Patients with neurological deficits should have deficits that are stable for a minimum of 1 week prior to registration
21. Patients who are on dexamethasone must be on a stable or decreasing dose for at least one week prior to registration
22. Patients must have fully recovered from the acute toxic effects of chemotherapy, immunotherapy, or radiotherapy prior to entering this study
23. Patients must have received their last dose of known myelosuppressive anticancer chemotherapy at least 21 days prior to study registration or at least six weeks if nitrosourea; at least two weeks must have lapsed if patients received lower dose oral etoposide (50 mg/2) without experiencing evidence of myelosuppression (i.e. neutropenia or requiring transfusion with blood products)
24. Patient must have recovered from any toxicity potentially related to the agent and received their last dose of the biologic agent >= 7 days prior to study registration; for biologic agents that have a prolonged half-life, the appropriate interval since last treatment should be discussed with the study chair prior to registration
25. At least three half-lives must have elapsed prior to registration; such patients should be discussed with the study chair prior to registration
26. Patient has received radiation therapy prior to study registration; patients must have had their last fraction of local irradiation to the primary tumor >= 3 months prior to registration, their last fraction of craniospinal irradiation (>= 24 Gy) or total body irradiation >= 3 months prior to registration or >= 6 weeks (wks) for the therapeutic doses of MIBG; patient has not received focal irradiation for symptomatic metastatic sites within 14 days prior to registration
27. Patient must be >= 3 months since high dose chemotherapy and peripheral blood stem cell rescue prior to registration
28. Autologous stem cell transplant following myeloablative therapy within 3 months prior to the first dose of abemaciclib or prior allogeneic stem cell transplant at any time; patients who received stem cell reinfusion following non-myeloablative therapy are eligible once they meet peripheral blood count criteria
29. Patients must be off all colony forming growth factors(s) for at least 1 week prior to registration (filgrastim, sargramostim, erythropoietin) and at least 2 weeks for long-acting formulations (e.g. NEULASTA)

Treatment Sites in Georgia