NCT03515200

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

• Status: Terminated
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 12 (actual)
• Sponsor: St. Jude Children's Research Hospital · Academic / Other
• Sex: All
• Age: 21 Years
• Healthy volunteers: Not accepted

Summary

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.

Detailed description

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.

Conditions

• Acute Lymphoblastic Leukemia, in Relapse
• Acute Lymphoblastic Leukemia With Failed Remission

Interventions

Type	Name	Description
DRUG	Palbociclib Oral Capsule	Given orally or nasogastrically (NG).
DRUG	Intrathecal Triple Therapy	Given intrathecally (IT).
DRUG	Dexamethasone	Given orally, nasogastrically (NG) or intravenously (IV).
DRUG	Bortezomib	Given intravenously (IV) or subcutaneously (SC).
DRUG	Dasatinib	Given orally or nasogastrically (NG).
DRUG	Doxorubicin	Given intravenously (IV).
DRUG	Ruxolitinib	Given orally or nasogastrically (NG).

Timeline

• Start date: 2018-04-20
• Primary completion: 2020-07-29
• Completion: 2020-07-29
• First posted: 2018-05-03
• Last updated: 2020-09-01

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study