Clinical Trials /

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

NCT03792256

Description:

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.

Related Conditions:
  • B-Cell Lymphoblastic Leukemia/Lymphoma
  • T-Cell Lymphoblastic Leukemia/Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: AINV18P1
  • NCT ID: NCT03792256

Conditions

  • Leukemia, Lymphocytic
  • Lymphoblastic Lymphoma
  • T-cell Lymphoma
  • T-cell Leukemia
  • Recurrent Disease
  • Acute Leukemia

Interventions

DrugSynonymsArms
PalbociclibTreatment (Palbociclib)
CytarabineTreatment (Palbociclib)
MethotrexateTreatment (Palbociclib)
HydrocortisoneTreatment (Palbociclib)
DoxorubicinTreatment (Palbociclib)
PrednisoloneTreatment (Palbociclib)
VincristineTreatment (Palbociclib)
PegaspargaseTreatment (Palbociclib)

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (Palbociclib)ExperimentalPatients 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.
  • Palbociclib
  • Cytarabine
  • Methotrexate
  • Hydrocortisone
  • Doxorubicin
  • Prednisolone
  • Vincristine
  • Pegaspargase

Eligibility 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.
      
Maximum Eligible Age:31 Years
Minimum Eligible Age:12 Months
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD) of Palbociclib
Time Frame:Up to 32 days
Safety Issue:
Description:MTD will be the maximum dose at which fewer than one-third of patients experience dose limiting toxicities.

Secondary Outcome Measures

Measure:Antitumor activity of palbociclib as assessed by response rates at the end of the treatment cycle.
Time Frame:Day 32
Safety Issue:
Description: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.
Measure:Antitumor activity of palbociclib as assessed by absolute peripheral blast count.
Time Frame:Baseline and after 72 hours
Safety Issue:
Description: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.
Measure:Antitumor activity of palbociclib as assessed by response rates at the end of the treatment cycle.
Time Frame:Day 32
Safety Issue:
Description: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.
Measure:Biologic activity of palbociclib will be assessed with assays measuring cell cycle inhibition.
Time Frame:Day 4
Safety Issue:
Description: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).
Measure:Biologic activity of palbociclib will be assessed with assays measuring cell cycle inhibition.
Time Frame:Day 32
Safety Issue:
Description: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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Children's Oncology Group

Last Updated

October 30, 2019