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.
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.
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.
- Patients with recurrent or refractory B- or T-lineage lymphoblastic leukemia and
- 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
- 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
- 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
- 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
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
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
- 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)
- 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
- 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
- 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.