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

Acute Leukemia Clinical Trial

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 Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03792256
• Other study ID #: AINV18P1
• Secondary ID: NCI-2019-02774
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: April 11, 2019
• Est. completion date: June 30, 2025

Study information

• Verified date: June 2021
• Source: Children's Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 15
• Est. completion date: June 30, 2025
• Est. primary completion date: June 30, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Months to 31 Years

Eligibility

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.

Related Conditions & MeSH terms

• Acute Leukemia
• Leukemia
• Leukemia, Lymphocytic
• Leukemia, Lymphoid
• Leukemia, T-Cell
• Lymphoblastic Lymphoma
• Lymphoma
• Lymphoma, Non-Hodgkin
• Precursor Cell Lymphoblastic Leukemia-Lymphoma
• Recurrent Disease
• T-cell Leukemia
• T-cell Lymphoma

Intervention

Drug:
• Palbociclib
Given PO (or via NG- tube)
• Cytarabine
Given intrathecally (IT)
• Methotrexate
Given intrathecally (IT)
• Hydrocortisone
Given IT
• Doxorubicin
Given intravenously (IV)
• Prednisolone
Either prednisone or prednisolone is given PO
• Vincristine
Given IV
• Pegaspargase
Given IV
• Hydrocortisone
Given intrathecally (IT)
• Prednisone
Either prednisone or prednisolone is given PO

Locations

Country	Name	City	State
United States	C S Mott Children's Hospital	Ann Arbor	Michigan
United States	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia
United States	Children's Hospital Colorado	Aurora	Colorado
United States	Children's Hospital of Alabama	Birmingham	Alabama
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Riley Hospital for Children	Indianapolis	Indiana
United States	Loma Linda University Medical Center	Loma Linda	California
United States	Saint Jude Children's Research Hospital	Memphis	Tennessee
United States	University of Minnesota/Masonic Cancer Center	Minneapolis	Minnesota
United States	Laura and Isaac Perlmutter Cancer Center at NYU Langone	New York	New York
United States	NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center	New York	New York
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Children's Hospital of Orange County	Orange	California
United States	Lucile Packard Children's Hospital Stanford University	Palo Alto	California
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania
United States	Primary Children's Hospital	Salt Lake City	Utah
United States	Seattle Children's Hospital	Seattle	Washington
United States	Children's National Medical Center	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Children's Oncology Group

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Frequency of dose limiting toxicities of Palbociclib	The frequency (%) of patients experiencing a dose limiting toxicity at least possibly attributable to Palbociclib by study part and dose level.	Up to 32 days
Primary	Frequency of adverse events of Palbociclib	The frequency (%) of patients experiencing adverse events at least possibly attributable to Palbociclib by study part and dose level.	Up to 4 years
Primary	Area under the drug concentration curve of Palbociclib	The median (min,max) of the area under the drug concentration curve for Palbociclib by study part and dose level.	Up to 11 days
Primary	Half-life of Palbociclib	The median (min,max) of the half-life of Palbociclib by study part and dose level	Up to 11 days
Primary	Maximum serum concentration of Palbociclib	Median (min,max) of the maximum serum concentration of Palbociclib by study part and dose level	Up to 11 days
Primary	Minimum serum concentration of Palbociclib	Median (min,max) of the minimum serum concentration of Palbociclib by study part and dose level	Up to 11 days
Primary	Clearance of Palbociclib	Median (min,max) of the clearance of Palbociclib by study part and dose level	Up to 11 days
Secondary	Antitumor effect of Palbociclib	Frequency (%) of patients with at least partial response to Palbociclib by study part and dose level.	Up to 4 years
Secondary	Absolute peripheral blast count of palbociclib	Median (min, max) of absolute peripheral blast count of palbociclib by study part and dose level	Up to 3 days
Secondary	Radiographic response of palbociclib in patients with LL patients	Frequency (%) of LL patients with radiographic response by study part and dose level	Day 32
Secondary	RB1 expression of palbociclib	Median (min,max) of RB1 expression of palbociclib by study part and dose level	Up to 4 days
Secondary	Phospho-RB1 expression of palbociclib	Median (min,max) of Phospho-RB1 expression of palbociclib by study part and dose level	Up to 4 days
Secondary	Cyclin D3 expression of palbociclib	Median (min,max) of Cyclin D3 expression of palbociclib by study part and dose level	Up to 4 days
Secondary	CDK4 expression of palbociclib	Median (min,max) of CDK4 expression of palbociclib by study part and dose level	Up to 4 days
Secondary	CDK6 expression of palbociclib	Median (min,max) of CDK6 expression of palbociclib by study part and dose level	Up to 4 days
Secondary	p27Kip1 expression of palbociclib	Median (min,max) of p27Kip1 expression of palbociclib by study part and dose level	Up to 4 days
Secondary	CD1a biological activity of palbociclib	Median (min,max) of CD1a biological activity of palbociclib	Up to 32 days
Secondary	CD3 biological activity of palbociclib	Median (min,max) of CD3 biological activity of palbociclib	Up to 32 days
Secondary	CD4 biological activity of palbociclib	Median (min,max) of CD4 biological activity of palbociclib	Up to 32 days
Secondary	CD8 biological activity of palbociclib	Median (min,max) of CD8 biological activity of palbociclib	Up to 32 days
Secondary	Ki67 biological activity of palbociclib	Median (min,max) of Ki67 biological activity of palbociclib	Up to 32 days
Secondary	DAPI biological activity of palbociclib	Median (min,max) of DAPI biological activity of palbociclib	Up to 32 days