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This study will be done in two parts: Part 1: Dose escalation and Part 2: Dose expansion.

In Part 1 - Dose escalation: Patients that lack Ph+ or Ph-like ALL, palbociclib, initially at 50mg/m2/day, 40% of the adult MTD, will be administered on Days 1-5 and 11-15, and escalated based on tolerability. If our highest dosing of 100mg/m2/day is tolerated, we will have a final dose level that receives an additional 10 days of palbociclib (Days 1-5, 11-15, and 21-30).

For patients that are Ph+ or have Ph-like ALL that are also receiving dasatinib or ruxolitinib: palbociclib, initially at 75mg/m2/day, 60% of the adult MTD, will be administered on Days 1-5 and 11-15 and escalated based on tolerability.

In Part 2 - Dose expansion: After determination of dose in Part 1, an additional 10 patients will be enrolled to confirm tolerability.

Palbociclib Oral Capsule

Intrathecal Triple Therapy

Given orally, nasogastrically (NG) or intravenously (IV).

Given intravenously (IV) or subcutaneously (SC).

Ruxolitinib

Tanja A. Gruber, MD, PhD

Leukemia cells grow and divide fast and out of control. In normal cells, certain proteins called CDK4 and CDK6 control cell growth. The study drug called palbociclib works by blocking the CDK4 and CDK6 proteins. Palbociclib has been shown to kill leukemia cells in the laboratory and in animal studies. Palbociclib will be added to other chemotherapy drugs, such as dexamethasone, that are known to be effective in treating childhood ALL.

This study will be done in two parts: Part 1: Dose Escalation and Part 2: Dose Expansion. The goal of Part 1 of the study is to find the highest tolerable combination of palbociclib and chemotherapy that the investigators can give to patients with leukemia. Once those doses are determined, the investigators will enroll patients on Part 2: Dose Expansion. This phase will enroll additional patients that receive the highest tolerated dose of palbociclib as determined in part 1, in order to better understand the side effects and how effective this treatment approach is.

With this research study, the investigators hope to meet the following goals:

* To find the highest tolerable dose of palbociclib in combination with chemotherapy that can be given without causing severe side effects;
* To learn what kind of side effects palbociclib in combination with chemotherapy may have; and
* To learn more about the biology effects of palbociclib on the cells in the participant's body.

Up to 40 children, adolescents and young adults will participate in both parts of this study at St. Jude only.

RELPALL is a single center, St Jude initiated, non-randomized single-arm phase I study to characterize the toxicity profile and to determine the maximum tolerated combination (MTC) and recommended phase II combination of palbociclib when given with chemotherapy in pediatric patients with relapsed or refractory acute lymphoblastic leukemia (ALL). Palbociclib is a reversible inhibitor of cyclin-dependent kinase 4 (CDK4) and the closely related cyclin-depending kinase 6 (CDK6) that has shown high anti-leukemic activity in several pre-clinical models. The mechanism of palbociclib, which reversibly arrests cells in G1, argues that combination treatment, as opposed to single agent treatment, will be more likely to provide clinical benefit. Timing of combination treatment with standard cytotoxic chemotherapy drugs that kill actively dividing cells is important to maximize the chance of activity. This study will build on prior multiple myeloma experience with palbociclib in combination with dexamethasone and bortezomib while tailoring the treatment to pediatric relapsed/refractory ALL. To maximize G1 arrest, dexamethasone will be given concurrently with palbociclib for five days. Patients will receive a 48 hour "washout" before receiving bortezomib and doxorubicin, both cytotoxic anti-leukemic drugs that preferentially kills cells when synchronized in S phase. Patients with Philadelphia Chromosome positive ALL (Ph+) and Philadelphia-like (Ph-like) ALL will also receive a tyrosine kinase inhibitor (TKI) beginning on Day 7 until count recovery. The primary objective is to determine a tolerable combination of palbociclib plus chemotherapy in pediatric patients with relapsed or refractory ALL. The secondary objective is to estimate the overall response rate to the combination of palbociclib and chemotherapy in pediatric patients with relapsed or refractory ALL. Exploratory objectives include measuring cell cycle kinetics of ALL cells following administration of palbociclib and an evaluation of modes of resistance in non-responders.

Palbociclib will be administered orally on Days 1-5, and 11-15 concurrently with dexamethasone of each 30 day cycle for one cycle (dose escalation) or up to 3 cycles for responders (dose expansion). Bortezomib will be given on Days 7, 10, 17 and 20. Doxorubicin will be given on Days 7 and 17. If the dose escalation with this schema is tolerated, a final dose level administering additional doses of palbociclib on days 21-30 will be evaluated.

Patients with Ph-like or Ph+ ALL will receive tyrosine kinase inhibitor (TKI) beginning on Day 7.

Triple intrathecal chemotherapy (MHA) will be given on Day 1 of the course. The frequency and total number of IT MHA is based on the patient's level of CNS disease.

Treatment With Combination Chemotherapy for Relapsed or Refractory Acute Lymphoblastic Leukemia

A Phase I Study of Palbociclib in Combination With Chemotherapy in Pediatric Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia

Determine a tolerable combination of palbociclib plus chemotherapy in pediatric patients with relapsed or refractory ALL.

percentage of patients who attain complete remission (CR)

Pfizer

St. Jude Children's Research Hospital

Spots Global Cancer Trial Database for intrathecal triple therapy