Clinical Trials /

Treatment With Combination Chemotherapy for Relapsed or Refractory Acute Lymphoblastic Leukemia

NCT03515200

Description:

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.

Related Conditions:
  • Acute Lymphoblastic Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Treatment With Combination Chemotherapy for Relapsed or Refractory Acute Lymphoblastic Leukemia
  • Official Title: A Phase I Study of Palbociclib in Combination With Chemotherapy in Pediatric Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia

Clinical Trial IDs

  • ORG STUDY ID: RELPALL
  • SECONDARY ID: NCI-2018-00814
  • NCT ID: NCT03515200

Conditions

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

Interventions

DrugSynonymsArms
Palbociclib Oral CapsuleIbrance®Treatment
Intrathecal Triple TherapyITMHA, methotrexate/hydrocortisone/cytarabineTreatment
DexamethasoneDecadronTreatment
BortezomibVelcade®Treatment
DasatinibSprycel®Treatment
DoxorubicinAdriamycin®Treatment
RuxolitinibJakafi®Treatment

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
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.
  • Palbociclib Oral Capsule
  • Intrathecal Triple Therapy
  • Dexamethasone
  • Bortezomib
  • Dasatinib
  • Doxorubicin
  • Ruxolitinib

Eligibility Criteria

        Inclusion Criteria:

        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.

        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.

        Exclusion Criteria:

        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.

        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.
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD) of palbociclib plus chemotherapy
Time Frame:End of cycle 1 (day 40 of therapy)
Safety Issue:
Description:Determine a tolerable combination of palbociclib plus chemotherapy in pediatric patients with relapsed or refractory ALL.

Secondary Outcome Measures

Measure:Treatment response
Time Frame: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)
Safety Issue:
Description:percentage of patients who attain complete remission (CR)

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:St. Jude Children's Research Hospital

Last Updated

October 16, 2019