Treatment With Combination Chemotherapy for Relapsed or Refractory Acute Lymphoblastic Leukemia

NCT03515200 | Terminated Phase 1 FDA Drug

• 2 other identifiers: RELPALLNCI-2018-00814
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

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

Outcome Measures

Primary Outcomes (1)

• Maximum tolerated dose (MTD) of palbociclib plus chemotherapy

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

  End of cycle 1 (day 40 of therapy)

Secondary Outcomes (1)

• Treatment response

  During the dose expansion phase, following completion of chemotherapy doses and prior to the subsequent course up to 3 cycles, if applicable (each cycle is 30 days)

Study Arms (1)

Treatment

EXPERIMENTAL

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.

Drug: Palbociclib Oral Capsule; Drug: Intrathecal Triple Therapy; Drug: Dexamethasone; Drug: Bortezomib; Drug: Dasatinib; Drug: Doxorubicin; Drug: Ruxolitinib

Interventions

Palbociclib Oral Capsule DRUG

Given orally or nasogastrically (NG).

Also known as: Ibrance®

Treatment

Intrathecal Triple Therapy DRUG

Given intrathecally (IT).

Also known as: ITMHA, methotrexate/hydrocortisone/cytarabine

Treatment

Dexamethasone DRUG

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

Also known as: Decadron

Treatment

Bortezomib DRUG

Given intravenously (IV) or subcutaneously (SC).

Also known as: Velcade®

Treatment

Dasatinib DRUG

Given orally or nasogastrically (NG).

Also known as: Sprycel®

Treatment

Doxorubicin DRUG

Given intravenously (IV).

Also known as: Adriamycin®

Treatment

Ruxolitinib DRUG

Given orally or nasogastrically (NG).

Also known as: Jakafi®

Treatment

Eligibility Criteria

• Age: Up to 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Participants must be \< 22 years of age.
• Diagnosis:
• Participants must have a diagnosis of acute lymphoblastic leukemia and disease meets at least one of the following criteria:
• relapsed or refractory to chemotherapy as defined by ≥5% leukemic blasts in the bone marrow or flow cytometry confirmed leukemic blasts in the peripheral blood
• relapsed after hematopoietic stem cell transplantation (HSCT)
• Patients must have had histologic, morphologic or flow cytometric verification of the malignancy at relapse.
• Performance Level:
• Karnofsky or Lansky performance score is ≥ 50% (corresponding to ECOG Score of ≤ 2). The Lansky performance score should be used for participants \< 16 years and the Karnofsky performance score for participants ≥ 16 years. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
• Prior Therapy:
• Patients who relapse while receiving standard ALL maintenance chemotherapy will not be required to have a waiting period before entry onto this study.

You may not qualify if:

• At least 14 days must have elapsed since the completion of cytotoxic therapy, with the exception of standard maintenance therapy and steroids.
• At least 7 days must have elapsed since completion of therapy with a biologic agent. For agents that have known adverse events occurring beyond 7 days after administration, this period prior to enrollment must be extended beyond the time during which adverse events are known to occur.
• At least 42 days must have elapsed since CAR-T cell therapy.
• At least 90 days have elapsed since bone marrow transplant and participant is off immune suppression for ≥ 2 weeks, if applicable with no evidence of active GVHD.
• At least 2 weeks must have elapsed since local XRT (small port); ≥ 3 months must have elapsed if prior cranial or craniospinal XRT was received, if ≥ 50% of the pelvis was irradiated, or if TBI was received; ≥ 6 weeks must have elapsed if other substantial bone marrow irradiation was given.
• Organ Function Requirements:
• Adequate renal function defined as glomerular filtration rate ≥ 60 cc/min/1.73m2 or serum creatinine based on age as follows:
• Age: \<6 months; maximum serum creatinine (mg/dL): 0.4 (male, female); Age: 6 months to \<1 year; maximum serum creatinine (mg/dL): 0.5 (male, female); Age: 1 to \< 2 years; maximum serum creatinine (mg/dL): 0.6 (male, female); Age: 2 to \< 6 years; maximum serum creatinine (mg/dL): 0.8 (male, female); Age: 6 to \<10 years; maximum serum creatinine (mg/dL): 1 (male, female); Age: 10 to \<13 years; maximum serum creatinine (mg/dL): 1.2 (male, female); Age: 13 to \<16 years; maximum serum creatinine (mg/dL): 1.5 (male), 1.4 (female); Age: ≥ 16 years; maximum serum creatinine (mg/dL): 1.7 (male), 1.4 (female)
• Adequate hepatic function defined as:
• Total bilirubin ≤ 2 x upper limit of normal (ULN) for age, and
• ALT ≤ 3 x ULN for age, unless elevation is due to leukemic infiltration.
• Adequate cardiac function defined as shortening fraction of ≥ 27% or ejection fraction ≥ 45%.
• Adequate pulmonary function defined as:
• No evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry \> 94%.
• No evidence of acute pulmonary infiltrates on chest radiograph.

Sponsors & Collaborators

• St. Jude Children's Research Hospital: lead
• Pfizer: collaborator

Study Sites (1)

St. Jude Children's Research Hospital

Memphis, Tennessee, 38105, United States

Location

Related Links

• St. Jude Children's Research Hospital
• Clinical Trials Open at St. Jude

MeSH Terms

Conditions

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Interventions

palbociclib; Methotrexate; Dexamethasone; Calcium Dobesilate; Bortezomib; Dasatinib; Doxorubicin; ruxolitinib

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Benzenesulfonates; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Arylsulfonates; Arylsulfonic Acids; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Boronic Acids; Acids, Noncarboxylic; Acids; Inorganic Chemicals; Boron Compounds; Pyrazines; Heterocyclic Compounds, 1-Ring; Thiazoles; Azoles; Pyrimidines; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Aminoglycosides; Glycosides; Carbohydrates

Study Officials

• Tanja A. Gruber, MD, PhD

  St. Jude Children's Research Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: April 19, 2018
• First Posted: May 3, 2018
• Study Start: April 20, 2018
• Primary Completion: July 29, 2020
• Study Completion: July 29, 2020
• Last Updated: September 1, 2020

Record last verified: 2020-08

Locations

US (1)