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Acute Lymphoblastic Leukemia, in RelapsePhase 1NCT03515200

Treatment With Combination Chemotherapy for Relapsed or Refractory Acute Lymphoblastic Leukemia

A Phase 1 study testing Palbociclib Oral Capsule, Intrathecal Triple Therapy and Dexamethasone in people with Acute Lymphoblastic Leukemia, in Relapse and Acute Lymphoblastic Leukemia With Failed Remission, run by St. Jude Children's Research Hospital at 1 site in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages Up to 21 years
What is being tested?
Palbociclib Oral Capsule, Intrathecal Triple Therapy and Dexamethasone
Could I receive a placebo?
No, everyone receives an active treatment
How many people
12 participants
Where
1 siteUnited States
Study dates
20 Apr 2018to 29 Jul 2020
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages Up to 21 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • 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.
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  • 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.
  • Patients who relapse on therapy other than standard ALL maintenance must have fully recovered from the acute toxic effects of all prior anti-cancer therapy, defined as resolution of all such toxicities to ≤ Grade 2 or lower per the inclusion/exclusion criteria prior to entering this study.
  • 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 3 half-lives must have elapsed since prior therapy that included a monoclonal antibody with the exception of blinatumomab. Patients must have been off blinatumomab infusion for at least 7 days and all drug related toxicity must have resolved to grade 2 or lower as outlined in the inclusion/exclusion criteria.
  • 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.
  • Adequate central nervous system (CNS) function defined as:
  • Patients with seizure disorder may be enrolled if on allowed anti-convulsants and well controlled. Benzodiazepines and gabapentin are acceptable.
  • CNS toxicity < Grade 2
  • Adequate peripheral nervous system (PNS) function defined as:
  • PNS toxicity < Grade 2.

Who cannot join

  • Extramedullary disease status: patients with isolated CNS disease or isolated testicular disease are not eligible.
  • Concurrent chemotherapy or targeted anti-cancer agents, other than intrathecal therapy.
  • Patients who have previously received bortezomib or other proteasome inhibitors that did not have a response while receiving the inhibitor are not eligible. Patients that responded but had a subsequent relapse are eligible.
  • Patients who have previously received palbociclib or other CDK4/6 inhibitors are not eligible.
  • Patient with concurrent severe and/or uncontrolled medical conditions that, in the opinion of the investigator, may impair participation in the study or the evaluation of safety and/or efficacy.
  • Patients that have an active, uncontrolled infection are not eligible.
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  • Known HIV infection or active hepatitis B (defined as hepatitis B surface antigen-positive) or C (defined as hepatitis C antibody-positive).
  • Pregnant or lactating (female participant of childbearing potential must have negative serum or urine pregnancy test required within 7 days prior to start of treatment).
  • Male or female participant of reproductive potential must agree to use appropriate methods of contraception for the duration of study treatment and for at least 30 days after last dose of protocol treatment.
  • Cumulative anthracyclines must not exceed 450mg/m2 doxorubicin equivalents following completion of treatment on protocol. Therefore for patients receiving one course on protocol cumulative anthracyclines must be less than or equal to 400mg/m2 doxorubicin equivalents at the time of enrollment
  • Inability or unwillingness or research participant or legal guardian/representative to give written informed consent.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • St. Jude Children's Research Hospital

    Memphis, Tennessee, 38105

Other trials in United States

About this study

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

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.

Read more

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.

Read the 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.

Being tested
Palbociclib Oral Capsule, Intrathecal Triple Therapy, Dexamethasone, Bortezomib, Dasatinib
Medical subject headings
Precursor Cell Lymphoblastic Leukemia-Lymphoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Palbociclib Oral CapsuleDrug

    Also called Ibrance®

    Given orally or nasogastrically (NG).

  • Intrathecal Triple TherapyDrug

    Also called ITMHA, methotrexate/hydrocortisone/cytarabine

    Given intrathecally (IT).

  • DexamethasoneDrug

    Also called Decadron

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

  • BortezomibDrug

    Also called Velcade®

    Given intravenously (IV) or subcutaneously (SC).

  • DasatinibDrug

    Also called Sprycel®

    Given orally or nasogastrically (NG).

  • DoxorubicinDrug

    Also called Adriamycin®

    Given intravenously (IV).

  • RuxolitinibDrug

    Also called Jakafi®

    Given orally or nasogastrically (NG).

Study groups in NCT03515200
Study groupRoleWhat they receive
TreatmentExperimentalThis 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.
Receives: Drug: Palbociclib Oral Capsule; Drug: Intrathecal Triple Therapy; Drug: Dexamethasone; Drug: Bortezomib; Drug: Dasatinib; Drug: Doxorubicin; Drug: Ruxolitinib

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: End of cycle 1 (day 40 of therapy)

Secondary outcomes (1)

  1. Treatment response

    percentage of patients who attain complete remission (CR)

    Measured: 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)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted3 May 2018
  2. Study start20 Apr 2018
  3. Primary completion29 Jul 2020
  4. Study completion29 Jul 2020

Why it stopped: Due to departure of PI from St. Jude

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Model description
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.
Masking
None (open label)
Enrolment
12 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03515200
Sponsor's protocol ID
RELPALL
Other IDs
NCI-2018-00814
Status last verified
Aug 2020
First submitted
19 Apr 2018
Last updated
1 Sep 2020
Results posted
No
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Palbociclib Oral Capsule, Intrathecal Triple Therapy and Dexamethasone in people with Acute Lymphoblastic Leukemia, in Relapse and Acute Lymphoblastic Leukemia With Failed Remission, run by St. Jude Children's Research Hospital at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 32 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 1 Sep 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was stopped early (reason given: Due to departure of PI from St. Jude). Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Maximum tolerated dose (MTD) of palbociclib plus chemotherapy (time frame: End of cycle 1 (day 40 of therapy)). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03515200.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Sep 2020.

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