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Palbociclib in Combination With Chemotherapy in Treating Children With Relapsed Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic Lymphoma (LL)

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ClinicalTrials.gov Identifier: NCT03792256
Recruitment Status : Recruiting
First Posted : January 3, 2019
Last Update Posted : October 2, 2019
Sponsor:
Information provided by (Responsible Party):
Children's Oncology Group

Tracking Information
First Submitted Date  ICMJE November 29, 2018
First Posted Date  ICMJE January 3, 2019
Last Update Posted Date October 2, 2019
Actual Study Start Date  ICMJE April 11, 2019
Estimated Primary Completion Date September 30, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 31, 2018)
  • Maximum tolerated dose (MTD) of Palbociclib [ Time Frame: Up to 32 days ]
    MTD will be the maximum dose at which fewer than one-third of patients experience dose limiting toxicities.
  • Incidence of adverse events [ Time Frame: Up to 4 years ]
    Will be graded using the Common Terminology Criteria for Adverse Events version 4.0
  • Pharmacokinetics of palbociclib: Time to maximum plasma concentration (Tmax) [ Time Frame: Pre-dose, and at 1, 2, 4, 8 and 24 hours post-dose of palbociclib on Days 1 and 11 ]
    Palbociclib plasma concentrations will be measured after single agent administration as well as when combined with chemotherapy at a centralized laboratory using a validated liquid chromatography/tandem mass spectrometry assay. PK parameters (Tmax, Cmax, t1/2, AUC, Cl/F) of palbociclib will be calculated using standard non-compartmental or compartmental methods and summarized with descriptive summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit).
  • Pharmacokinetics of palbociclib: Maximum plasma concentration (Cmax) [ Time Frame: Pre-dose, and at 1, 2, 4, 8 and 24 hours post-dose of palbociclib on Days 1 and 11 ]
    Palbociclib plasma concentrations will be measured after single agent administration as well as when combined with chemotherapy at a centralized laboratory using a validated liquid chromatography/tandem mass spectrometry assay. PK parameters (Tmax, Cmax, t1/2, AUC, Cl/F) of palbociclib will be calculated using standard non-compartmental or compartmental methods and summarized with descriptive summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit).
  • Pharmacokinetics of palbociclib: Terminal phase half-life (t1/2) [ Time Frame: Pre-dose, and at 1, 2, 4, 8 and 24 hours post-dose of palbociclib on Days 1 and 11 ]
    Palbociclib plasma concentrations will be measured after single agent administration as well as when combined with chemotherapy at a centralized laboratory using a validated liquid chromatography/tandem mass spectrometry assay. PK parameters (Tmax, Cmax, t1/2, AUC, Cl/F) of palbociclib will be calculated using standard non-compartmental or compartmental methods and summarized with descriptive summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit).
  • Pharmacokinetics of palbociclib: Area under the plasma concentration (AUC) [ Time Frame: Pre-dose, and at 1, 2, 4, 8 and 24 hours post-dose of palbociclib on Days 1 and 11 ]
    Palbociclib plasma concentrations will be measured after single agent administration as well as when combined with chemotherapy at a centralized laboratory using a validated liquid chromatography/tandem mass spectrometry assay. PK parameters (Tmax, Cmax, t1/2, AUC, Cl/F) of palbociclib will be calculated using standard non-compartmental or compartmental methods and summarized with descriptive summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit).
  • Pharmacokinetics of palbociclib: Plasma Clearance (CI/F) [ Time Frame: Pre-dose, and at 1, 2, 4, 8 and 24 hours post-dose of palbociclib on Days 1 and 11 ]
    Palbociclib plasma concentrations will be measured after single agent administration as well as when combined with chemotherapy at a centralized laboratory using a validated liquid chromatography/tandem mass spectrometry assay. PK parameters (Tmax, Cmax, t1/2, AUC, Cl/F) of palbociclib will be calculated using standard non-compartmental or compartmental methods and summarized with descriptive summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit).
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03792256 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: December 31, 2018)
  • Antitumor activity of palbociclib as assessed by response rates at the end of the treatment cycle. [ Time Frame: Day 32 ]
    A bone marrow aspirate will be performed on Day 32 in patients with ALL and morphological bone marrow blast percentage will be determined. The clinical response of any extramedullary disease sites will also be assessed. The blast percentage in the bone marrow in conjunction with the clinical response in any involved extramedullary disease sites will be used to determine the overall response designation at the end of the treatment cycle in patients with ALL.
  • Antitumor activity of palbociclib as assessed by absolute peripheral blast count. [ Time Frame: Baseline and after 72 hours ]
    As an early measure of response to single agent palbociclib, the absolute peripheral blast count will be measured at baseline and after 72 hours of drug exposure in patients with ALL and peripheral blood circulating blasts >1000/mm^3.
  • Antitumor activity of palbociclib as assessed by response rates at the end of the treatment cycle. [ Time Frame: Day 32 ]
    Imaging studies will be performed on Day 32 in patients with LL. Morphological evaluation of the bone marrow (if involved at diagnosis) will also be performed on Day 32 in patients with LL. Disease response will be determined using the new International Pediatric Non-Hodgkin Lymphoma Response Criteria and the major response designations will be established by CT or MRI of involved sites in conjunction with morphologic evaluation of bone marrow (BM) if involved at diagnosis.
  • Biologic activity of palbociclib will be assessed with assays measuring cell cycle inhibition. [ Time Frame: Day 4 ]
    Bone marrow (or peripheral blood if the absolute blast count is >1000/mm3) samples will be collected pre-study and on Day 4 after 72 hours of single agent palbociclib exposure. Participation in these studies is optional. Expression of RB1, phospho-RB1, Cyclin D3, CDK4, CDK6 and p27Kip1 will be performed using Western Blotting (immunoblotting).
  • Biologic activity of palbociclib will be assessed with assays measuring cell cycle inhibition. [ Time Frame: Day 32 ]
    Cell cycle analyses will also be performed before and after drug exposure using standard flow cytometry methods combining surface staining for ALL markers (e.g., CD1a, CD3, CD4, CD8) and intracellular staining for the cell cycle (and apoptosis) markers Ki67 and DAPI. These assays will also be performed at the end of the treatment cycle in residual blasts in those patients who have failed to achieve remission.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Palbociclib in Combination With Chemotherapy in Treating Children With Relapsed Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic Lymphoma (LL)
Official Title  ICMJE A Phase 1 Study Of Palbociclib (IND#141416), A CDK 4/6 Inhibitor, In Combination With Chemotherapy In Children With Relapsed Acute Lymphoblastic Leukemia (ALL) Or Lymphoblastic Lymphoma (LL)
Brief Summary AINV18P1 is a Phase 1 study where palbociclib will be administrated in combination with a standard re-induction platform in pediatric relapsed Acute Lymphoblastic Leukemia (ALL) and lymphoblastic lymphoma (LL). LL patients are included because the patient population is rare and these patients are most commonly treated with ALL regimens. The proposed starting dose for this study will be 50 mg/m^2/day for 21 days.
Detailed Description

PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of palbociclib administered in combination with re-induction chemotherapy in pediatric patients with relapsed B- or T-lineage ALL/LL.

II. To define and describe the toxicities of palbociclib administered on this schedule.

III. To characterize the pharmacokinetics of palbociclib in pediatric patients with relapsed B- or T-lineage ALL/LL.

SECONDARY OBJECTIVES:

I. To preliminarily define the antitumor activity of palbociclib in combination with chemotherapy for children with relapsed ALL/LL within the confines of a Phase 1 study.

II. To assess the biologic activity of palbociclib in this patient population.

OUTLINE:

Patients receive Palbociclib PO (or via NG- tube) once daily on Days 1-21; Intrathecal cytarabine (IT ARAC) on Day 1, Doxorubicin IV push or infusion over 1-15 min on Day 4; Prednisone or prednisolone PO on days 4-31; Vincristine IV push or mini-bag per institutional policy on days 4, 11, 18, and 25; and Pegaspargase IV over 1-2 hours on Days 5, and 18. If CNS3 leukemia is present, patients receive Intrathecal Triple Therapy (ITT) on days 4, 11, 18, and 25. If CNS1 and 2 leukemia present, patient receive Methotrexate (IT MTX) on Days 18 and 32. Treatment will be given for one cycle, 32 days, in the absence of disease progression or unacceptable toxicity.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Leukemia, Lymphocytic
  • Lymphoblastic Lymphoma
  • T-cell Lymphoma
  • T-cell Leukemia
  • Recurrent Disease
  • Acute Leukemia
Intervention  ICMJE
  • Drug: Palbociclib
    Given PO (or via NG- tube)
  • Drug: Cytarabine
    Given IT
  • Drug: Methotrexate
    Given IT
  • Drug: Hydrocortisone
    Given IT
  • Drug: Doxorubicin
    Given IV
  • Drug: Prednisolone
    Given PO
  • Drug: Vincristine
    Given IV
  • Drug: Pegaspargase
    Given IV
Study Arms  ICMJE Experimental: Treatment (Palbociclib)
Patients receive Palbociclib 50 mg/m^2 (starting dose with maximum dose of 100 mg) PO (or via NG- tube) once daily on Days 1-21; Intrathecal cytarabine (IT ARAC) age-based dosing on Day 1, Doxorubicin 60 mg/m^2 IV push or infusion over 1-15 min on Day 4; Prednisone or prednisolone 40 mg/m^2 PO divided BID or TID on days 4-31; Vincristine 1.5 mg/m^2 (maximum dose 2 mg) IV push or mini-bag per institutional policy on days 4, 11, 18, and 25; and Pegaspargase 2500 IU/m^2 IV over 1-2 hours on Days 5, and 18. If CNS3 leukemia is present, patients receive Intrathecal Triple Therapy (ITT) age-based dosing on days 4, 11, 18, and 25. If CNS1 and 2 leukemia present, patient receive Methotrexate (IT MTX) age-based dosing on Days 18 and 32. Treatment will be given for one cycle, 32 days, in the absence of disease progression or unacceptable toxicity.
Interventions:
  • Drug: Palbociclib
  • Drug: Cytarabine
  • Drug: Methotrexate
  • Drug: Hydrocortisone
  • Drug: Doxorubicin
  • Drug: Prednisolone
  • Drug: Vincristine
  • Drug: Pegaspargase
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: December 31, 2018)
15
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 30, 2020
Estimated Primary Completion Date September 30, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patients with recurrent or refractory B- or T-lineage lymphoblastic leukemia and lymphoma.
  • Patients with leukemia must have ≥ 5% (M2 or M3) bone marrow blasts with or without an extramedullary site of relapse. Morphologic relapse for M2 should be confirmed using flow cytometry, FISH and/or cytogenetics or molecular techniques.
  • Patients with LL must have either measurable or evaluable disease.
  • Patients with first or greater relapsed T-lineage ALL or LL and second or greater relapsed B-lineage ALL or LL are eligible.
  • Patients with primary refractory disease with at least 2 prior induction attempts or first relapse refractory to at least one prior re-induction attempt are eligible.
  • Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 for patients <= 16 years of age.

    • Note: 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.
  • Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment. If after the required timeframe, the numerical eligibility criteria are met, e.g., blood count criteria, the patient is considered to have recovered adequately.

    1. Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive. See DVL homepage for commercial and Phase 1 investigational agent classifications. For agents not listed, the duration of this interval must be discussed with the study chair and the study-assigned Research Coordinator prior to enrollment.

      • A waiting period prior to enrollment is not required for patients receiving standard cytotoxic maintenance chemotherapy (i.e., corticosteroid, vincristine, 6MP, and/or methotrexate).
      • Intrathecal cytotoxic therapy: No waiting period is required for patients having received intrathecal cytarabine, methotrexate, and/or hydrocortisone. Intrathecal chemotherapy given at the time of diagnostic LP to evaluate for relapse prior to study enrollment is allowed.

        • 14 days must have elapsed after the completion of other cytotoxic therapy, with the exception of hydroxyurea, for patients not receiving standard maintenance therapy. Additionally, patients must have fully recovered from all acute toxic effects of prior therapy.

          • NOTE: Cytoreduction with hydroxyurea in patients can be initiated and continued for up to 24 hours prior to the start of protocol therapy.
          • Note: Intrathecal chemotherapy that is given up to 72 hours prior to initiation of systemic chemotherapy per AINV18P1 counts as protocol therapy and not prior anti-cancer therapy. Intrathecal chemotherapy given > 72 hours prior does not count as protocol therapy.
    2. Anti-cancer agents not known to be myelosuppressive (e.g. not associated with reduced platelet or ANC counts): >= 7 days after the last dose of agent. See DVL homepage for commercial and Phase 1 investigational agent classifications. For agents not listed, the duration of this interval must be discussed with the study chair and the study-assigned Research Coordinator prior to enrollment.

      • NOTE: Cytoreduction with prednisone or methylprednisolone for <= 120 hours (5 days) in patients can be initiated and continued for up to 24 hours prior to the start of protocol therapy.
    3. Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody with the exception of blinatumomab, and toxicity related to prior antibody therapy must be recovered to Grade <= 1. Patients must have been off blinatumomab infusion for at least 14 days and all drug related toxicity must have resolved to Grade <= 1.
    4. Corticosteroids: If used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid and toxicity related to prior immune therapy must be recovered to Grade <= 1 off corticosteroids.
    5. Hematopoietic growth factors: >= 14 days after the last dose of a long-acting growth factor (e.g. pegfilgrastim) or 7 days for short-acting growth factor. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair and the study-assigned Research Coordinator.
    6. Interleukins, Interferons and Cytokines (other than Hematopoietic Growth Factors): >= 21 days after the completion of interleukins, interferon or cytokines (other than Hematopoietic Growth Factors)
    7. Stem cell Infusions (with or without TBI):

      • Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem cell infusion including DLI or boost infusion: >= 84 days after infusion and no evidence of GVHD.
      • Autologous stem cell infusion including boost infusion: >= 42 days.
    8. Cellular Therapy: >= 30 days after the completion of any type of cellular therapy (e.g. modified T cells, NK cells, dendritic cells, etc.)
    9. XRT/External Beam Irradiation including Protons: >= 14 days after local XRT; >= 150 days after TBI, craniospinal XRT or if radiation to >= 50% of the pelvis; >= 42 days if other substantial BM radiation.
    10. Patients must not have received prior exposure to palbociclib or another CDK4/6 inhibitor.
  • Adequate Renal Function Defined as:

    • Creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73 m2 or
    • A serum creatinine based on age/gender as follows:

      • Age: 1 to < 2 years; Male: 0.6 mg/dL; Female: 0.6 mg/dL
      • Age: 2 to < 6 years; Male: 0.8 mg/dL; Female: 0.8 mg/dL
      • Age: 6 to < 10 years; Male: 1 mg/dL; Female: 1 mg/dL
      • Age: 10 to < 13 years; Male: 1.2 mg/dL; Female: 1.2 mg/dL
      • Age: 13 to < 16 years; Male: 1.5 mg/dL; Female: 1.4 mg/dL
      • Age: >= 16 years; Male: 1.7 mg/dL; Female: 1.4 mg/dL
  • Adequate Liver Function Defined as:

    • bilirubin (sum of conjugated + unconjugated) <= 1.5 x upper limit of normal (ULN) for age
    • SGPT (ALT) <= 225 U/L unless disease-related. For the purpose of this study, the ULN for SGPT is 45 U/L.
    • Serum albumin >= 2 g/dL.
  • Adequate Cardiac Function Defined As:

    • Shortening fraction of >= 27% by echocardiogram, or
    • Ejection fraction of >= 50% by gated radionuclide study.
  • All patients and/or their parents or legally authorized representatives must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines.

Exclusion Criteria:

  • Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies. Based on the mechanism of action, palbociclib may be expected to cause fetal harm if used during pregnancy. Pregnancy tests must be obtained in girls who are post-menarche. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method for the duration of study therapy. Women of reproductive potential should use effective contraception during treatment and for at least 3 weeks after the last dose of palbociclib. Males with female partners of reproductive potential should use effective contraception during treatment and for 3 months after the last dose of palbociclib. Animal data suggests that palbociclib may affect male fertility.
  • Prednisone or methylprednisolone for ≤ 120 hours (5 days) may be administered for cytoreduction up to 24 hours prior to the start of protocol therapy and as treatment for allergic reactions or for physiologic replacement/stress dosing of hydrocortisone for documented adrenal insufficiency. Corticosteroids are not allowed for other indications. If used to modify immune adverse events related to prior therapy, ≥ 14 days must have elapsed since last dose of corticosteroid.
  • Patients who are currently receiving another investigational drug.
  • Patients who are currently receiving other anti-cancer agents are not eligible [except patients receiving hydroxyurea, which may be continued until 24 hours prior to start of protocol therapy].
  • Patients who are currently receiving drugs that are strong inhibitors and/or inducers of CYP3A4 or sensitive CYP3A4 substrates and CYP3A4 substrates with a narrow therapeutic range are not eligible. Strong inducers or inhibitors of CYP3A4 are prohibited from 14 days prior to enrollment to the end of the study.
  • Patients who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post bone marrow transplant.
  • Patients must be able to swallow intact capsules or liquid. Patients that are unable to swallow oral medications may receive palbociclib through an NG tube. G tube administration is not allowed.
  • Patients who have an uncontrolled infection defined as below:

    • Fever above 38.2°C within 48 hours of study enrollment with clinical signs of infection. Fever that is determined to be due to tumor burden is allowed if patients have documented negative blood cultures for at least 48 hours prior to enrollment and no concurrent signs or symptoms of active infection or hemodynamic instability.
    • A positive fungal culture within 30 days of study enrollment or active therapy for presumed invasive fungal infection.
    • Patients may be receiving IV or oral antibiotics to complete a course of therapy for a prior documented infection as long as cultures have been negative for at least 48 hours and signs or symptoms of active infection have resolved. For patients with c. difficile diarrhea, at least 72 hours of antibacterial therapy must have elapsed and stools must have normalized to baseline.
    • Active viral or protozoal infection requiring IV treatment.
  • Patients known to have one of the following concomitant genetic syndromes: Down syndrome, Bloom syndrome, ataxia-telangiectasia, Fanconi anemia, Kostmann syndrome, Shwachmann syndrome or any other known bone marrow failure syndrome.
  • Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 12 Months to 31 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03792256
Other Study ID Numbers  ICMJE AINV18P1
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Children's Oncology Group
Study Sponsor  ICMJE Children's Oncology Group
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: Elizabeth Raetz, MD Children's Oncology Group
PRS Account Children's Oncology Group
Verification Date January 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP