Summary

This phase I trial studies the best dose and side effects of ribociclib when given with everolimus and dexamethasone, and to see how well they work in treating children and young adults with acute lymphoblastic leukemia that has come back (relapsed) or does not respond to treatment (refractory). Ribociclib and everolimus may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Anti-inflammatory drugs, such as dexamethasone lower the body’s immune response and are used with other drugs in the treatment of some types of cancer. Giving ribociclib together with everolimus and dexamethasone may work as a possible treatment for relapsed or refractory acute lymphoblastic leukemia.

Objectives

PRIMARY OBJECTIVES:
I. To determine the pharmacokinetic (PK) parameters of ribociclib in combination with dexamethasone in pediatric and young adult patients with relapsed/refractory ALL. (Cohort A)
II. To describe the toxicities of this combination in this patient population. (Cohort A)
III. To determine the dose limiting toxicities and maximum tolerated dose or recommended dose for expansion (RDE) of ribociclib in combination with everolimus and dexamethasone in pediatric and young adult patients with relapsed/refractory ALL. (Cohort B)
IV. To determine the PK parameters of ribociclib in combination with everolimus and dexamethasone in this population. (Cohort B)
V. To further explore the safety and tolerability of ribociclib in combination with everolimus and dexamethasone in pediatric and young adult patients with relapsed/refractory ALL. (Cohort C)
VI. To determine the PK parameters of ribociclib in combination with everolimus and dexamethasone in this population. (Cohort C)

SECONDARY OBJECTIVE:
I. To describe the preliminary anti-leukemic activity of the combinations of ribociclib, everolimus and dexamethasone.

EXPLORATORY OBJECTIVES:
I. To evaluate the pharmacodynamic effects of these regimens in peripheral blood and bone marrow samples.
II. To evaluate biomarkers of response to the combination of ribociclib, everolimus and dexamethasone in patients with relapsed acute lymphoblastic leukemia.

OUTLINE: This is a dose-escalation study of ribociclib. Patients are assigned to 1 of 2 cohorts.

COHORT A: Patients receive ribociclib orally (PO) daily on days 1-21 and dexamethasone intravenously (IV) or PO twice daily (BID) on days 1-5 and 11-15. Patients also receive intrathecal chemotherapy including methotrexate, cytarabine, and hydrocortisone on day 1. Patients with central nervous system (CNS)2 disease at the start of a cycle receive intrathecal chemotherapy again on day 15. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

COHORT B: Patients receive everolimus PO once daily (QD) on days 1-21. Patients also receive ribociclib, dexamethasone, and intrathecal chemotherapy as in Cohort A. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, 1 year, and 2 years.

Eligibility

1. Histologically confirmed diagnosis of either: 1) relapsed or refractory acute lymphoblastic leukemia (ALL) or 2) chronic lymphocytic leukemia [CML] in lymphoid blast crisis (must have failed at least 2 lines of tyrosine kinase inhibitor [TKI] therapy). : * Primary refractory disease: Persistent disease after at least two induction attempts * Relapsed disease: Second or subsequent relapse, or any relapse refractory to salvage chemotherapy
2. Participants must have bone marrow with >= 1% lymphoblasts definitively identified either on a bone marrow aspirate or biopsy sample, as assessed by morphology, immunohistochemical studies, flow cytometry, karyotype, cytogenetic testing such as fluorescent in situ hybridization (FISH) or other molecular studies.
3. Participants with CNS 1 or CNS 2 disease are eligible. Patients with isolated CNS relapse or CNS 3 disease are not eligible.
4. Participants must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study and meet all of the following criteria: * Corticosteroids: The following uses of corticosteroids are permitted: single doses (e.g., during anesthesia), topical applications (e.g., for rash), inhaled sprays (e.g., for obstructive airway diseases, asthma), eye drops or local injections (e.g., intra-articular), or physiological replacement steroids (i.e., hydrocortisone for treatment of adrenal insufficiency). For Cohort C only: 14 days must have elapsed since the completion of systemic corticosteroid administration. * Myelosuppressive chemotherapy: 14 days must have elapsed since the completion of myelosuppressive therapy. Individuals may have received any of the following medications within 14 days without a “wash-out” period: ** Standard maintenance therapy dosing of vincristine, 6MP, low dose methotrexate. ** Hydroxyurea. ** Intrathecal chemotherapy with methotrexate, hydrocortisone and/or cytarabine. * Radiation therapy (XRT): ** Total body irradiation (TBI) or cranial radiation therapy: Must have been completed more than 90 days prior to study entry. ** XRT for chloroma does not require a washout period. ** Palliative XRT does not require a washout. * Small molecule inhibitors (BCR-ABL or FLT3 inhibitors, for example): 7 days must have elapsed since the completion of therapy. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair. * Immunotherapy: At least 6 weeks after the administration of any type of immunotherapy, including, but not limited to, tumor vaccines, chimeric antigen receptor (CAR) therapy, other immune effector cell therapy or checkpoint inhibitors. * Monoclonal antibodies: At least 3 half-lives of the antibody after the last dose of a monoclonal antibody. * Prior hematopoietic stem cell transplant (HSCT): Patients who have received HSCT are eligible, but must meet all of the following conditions: ** Autologous HSCT > 60 days of study entry ** Allogeneic HSCT > 90 days of study entry ** No evidence of graft-versus-host-disease (GVHD) ** Weaning or stable doses of calcineurin inhibitors are permitted provided there is no evidence of active GVHD.
5. Participants must have a body surface area (BSA) >= 0.4 m^2.
6. Performance status: * Lansky > 50 for individuals < 16 years old; Karnofsky > 50% for individuals >= 16 years old.
7. Direct bilirubin =< 1.5 X institutional upper limit of normal (ULN).
8. Alanine aminotransferase (ALT) < 3 x ULN for age and aspartate aminotransferase (AST) < 3 x ULN for age. Patients with leukemic infiltration of the liver must have AST and ALT < 5 x ULN for age.
9. Creatinine below institutional ULN or creatinine clearance > 60 mL/min/1.73 m^2 for subjects with creatinine levels above institutional normal.
10. Participants with a prior history of cardiac dysfunction must have an echocardiogram ejection fraction >= 50% prior to enrollment. Echocardiogram must be obtained while patient is not receiving cardiotropic medications (e.g., pressors or afterload reducers).
11. Corrected QT interval by Fridericia (QTcF) < 450 ms on screening electrocardiogram (ECG).
12. Oxygen saturation >= 90% by pulse oximetry without administration of supplemental oxygen.
13. Female patients of childbearing potential must have a negative urine or serum pregnancy test confirmed prior to enrollment.
14. Female patients with infants must agree not to breastfeed their infants while on this study.
15. 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, for the duration of study participation, and for 21 days after the last dose of the study drug. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
16. Ability to understand and/or the willingness of the patient (or parent or legally authorized representative, if minor) to provide informed consent, documented using an institutionally approved informed consent procedure.