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Trial record 1 of 1 for:    AINV18P1
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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 : April 7, 2020
Sponsor:
Information provided by (Responsible Party):
Children's Oncology Group

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 palbociclib starting dose for this study will be 50 mg/m^2/day for 21 days.

Condition or disease Intervention/treatment Phase
Leukemia, Lymphocytic Lymphoblastic Lymphoma T-cell Lymphoma T-cell Leukemia Recurrent Disease Acute Leukemia Drug: Palbociclib Drug: Cytarabine Drug: Methotrexate Drug: Hydrocortisone Drug: Doxorubicin Drug: Prednisolone Drug: Vincristine Drug: Pegaspargase Drug: Prednisone Phase 1

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 or 2 disease status, patients receive Methotrexate (IT MTX) on Days 18 and 32. Patients known to be CNS3 at study entry may receive ITT on Day 1 rather than IT ARAC. Treatment will be given for one cycle, 32 days, in the absence of disease progression or unacceptable toxicity.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 15 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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)
Actual Study Start Date : April 11, 2019
Estimated Primary Completion Date : September 30, 2020
Estimated Study Completion Date : September 30, 2020


Arm Intervention/treatment
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. Patients known to be CNS3 at study entry may receive ITT on Day 1 rather than IT ARAC. 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.
Drug: Palbociclib
Given PO (or via NG- tube)

Drug: Cytarabine
Given intrathecally (IT)

Drug: Methotrexate
Given intrathecally (IT)

Drug: Hydrocortisone
Given IT

Drug: Doxorubicin
Given intravenously (IV)

Drug: Prednisolone
Either prednisone or prednisolone is given PO

Drug: Vincristine
Given IV

Drug: Pegaspargase
Given IV

Drug: Hydrocortisone
Given intrathecally (IT)

Drug: Prednisone
Either prednisone or prednisolone is given PO




Primary Outcome Measures :
  1. Frequency of dose limiting toxicities of Palbociclib [ Time Frame: Up to 32 days ]
    The frequency (%) of patients experiencing a dose limiting toxicity at least possibly attributable to Palbociclib by study part and dose level.

  2. Frequency of adverse events of Palbociclib [ Time Frame: Up to 4 years ]
    The frequency (%) of patients experiencing adverse events at least possibly attributable to Palbociclib by study part and dose level.

  3. Area under the drug concentration curve of Palbociclib [ Time Frame: Up to 11 days ]
    The median (min,max) of the area under the drug concentration curve for Palbociclib by study part and dose level.

  4. Half-life of Palbociclib [ Time Frame: Up to 11 days ]
    The median (min,max) of the half-life of Palbociclib by study part and dose level

  5. Maximum serum concentration of Palbociclib [ Time Frame: Up to 11 days ]
    Median (min,max) of the maximum serum concentration of Palbociclib by study part and dose level

  6. Minimum serum concentration of Palbociclib [ Time Frame: Up to 11 days ]
    Median (min,max) of the minimum serum concentration of Palbociclib by study part and dose level

  7. Clearance of Palbociclib [ Time Frame: Up to 11 days ]
    Median (min,max) of the clearance of Palbociclib by study part and dose level


Secondary Outcome Measures :
  1. Antitumor effect of Palbociclib [ Time Frame: Up to 4 years ]
    Frequency (%) of patients with at least partial response to Palbociclib by study part and dose level.

  2. Absolute peripheral blast count of palbociclib [ Time Frame: Up to 3 days ]
    Median (min, max) of absolute peripheral blast count of palbociclib by study part and dose level

  3. Radiographic response of palbociclib in patients with LL patients [ Time Frame: Day 32 ]
    Frequency (%) of LL patients with radiographic response by study part and dose level

  4. RB1 expression of palbociclib [ Time Frame: Up to 4 days ]
    Median (min,max) of RB1 expression of palbociclib by study part and dose level

  5. Phospho-RB1 expression of palbociclib [ Time Frame: Up to 4 days ]
    Median (min,max) of Phospho-RB1 expression of palbociclib by study part and dose level

  6. Cyclin D3 expression of palbociclib [ Time Frame: Up to 4 days ]
    Median (min,max) of Cyclin D3 expression of palbociclib by study part and dose level

  7. CDK4 expression of palbociclib [ Time Frame: Up to 4 days ]
    Median (min,max) of CDK4 expression of palbociclib by study part and dose level

  8. CDK6 expression of palbociclib [ Time Frame: Up to 4 days ]
    Median (min,max) of CDK6 expression of palbociclib by study part and dose level

  9. p27Kip1 expression of palbociclib [ Time Frame: Up to 4 days ]
    Median (min,max) of p27Kip1 expression of palbociclib by study part and dose level

  10. CD1a biological activity of palbociclib [ Time Frame: Up to 32 days ]
    Median (min,max) of CD1a biological activity of palbociclib

  11. CD3 biological activity of palbociclib [ Time Frame: Up to 32 days ]
    Median (min,max) of CD3 biological activity of palbociclib

  12. CD4 biological activity of palbociclib [ Time Frame: Up to 32 days ]
    Median (min,max) of CD4 biological activity of palbociclib

  13. CD8 biological activity of palbociclib [ Time Frame: Up to 32 days ]
    Median (min,max) of CD8 biological activity of palbociclib

  14. Ki67 biological activity of palbociclib [ Time Frame: Up to 32 days ]
    Median (min,max) of Ki67 biological activity of palbociclib

  15. DAPI biological activity of palbociclib [ Time Frame: Up to 32 days ]
    Median (min,max) of DAPI biological activity of palbociclib



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   12 Months to 31 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03792256


Locations
Show Show 22 study locations
Sponsors and Collaborators
Children's Oncology Group
Investigators
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Study Chair: Elizabeth Raetz, MD Children's Oncology Group
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Responsible Party: Children's Oncology Group
ClinicalTrials.gov Identifier: NCT03792256    
Other Study ID Numbers: AINV18P1
NCI-2019-02774 ( Other Identifier: CTRP (Clinical Trial Reporting Program) )
First Posted: January 3, 2019    Key Record Dates
Last Update Posted: April 7, 2020
Last Verified: April 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Lymphoma
Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Lymphoma, Non-Hodgkin
Leukemia, T-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Cytarabine
Prednisone
Prednisolone
Hydrocortisone
Hydrocortisone 17-butyrate 21-propionate
Hydrocortisone acetate
Hydrocortisone hemisuccinate
Doxorubicin
Methotrexate
Vincristine
Palbociclib
Pegaspargase
Antibiotics, Antineoplastic
Antineoplastic Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action