Palbociclib in Treating Patients With Relapsed or Refractory Rb Positive Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With Activating Alterations in Cell Cycle Genes (A Pediatric MATCH Treatment Trial)

Phase 2

Completed

Conditions: Advanced Malignant Solid Neoplasm
Recurrent Childhood Ependymoma
Recurrent Glioma
Recurrent Hepatoblastoma
Recurrent Malignant Germ Cell Tumor
Recurrent Medulloblastoma
Refractory Ewing Sarcoma
Refractory Glioma
Refractory Osteosarcoma
Refractory Rhabdoid Tumor

Interventions: Other: Laboratory Biomarker Analysis
Drug: Palbociclib
Other: Pharmacological Study

Registration Number: NCT03526250

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: This phase II Pediatric MATCH trial studies how well palbociclib works in treating patients with Rb positive solid tumors, non-Hodgkin lymphoma, or histiocytic disorders with activating alterations (mutations) in cell cycle genes that have spread to other places in the body and have come back or do not respond to treatment. Palbociclib may stop the growth of cancer cells by blocking some of the proteins needed for cell growth.

Detailed Description: PRIMARY OBJECTIVE:

I. To determine the objective response rate (ORR; complete response + partial response) in pediatric patients treated with palbociclib with advanced solid tumors (including central nervous system \[CNS\] tumors), non-Hodgkin lymphomas or histiocytic disorders that harbor activating genetic alterations in cell cycle genes.

SECONDARY OBJECTIVES:

I. To estimate the progression free survival in pediatric patients treated with palbociclib with advanced solid tumors (including CNS tumors), non-Hodgkin lymphomas or histiocytic disorders that harbor activating genetic alterations in alterations in cell cycle genes.

II. To obtain information about the tolerability of palbociclib in children and adolescents with relapsed or refractory cancer.

EXPLORATORY OBJECTIVE:

I. To explore approaches to profiling changes in tumor genomics over time through evaluation of circulating tumor deoxyribonucleic acid (DNA).

OUTLINE:

Patients receive palbociclib orally (PO) once daily (QD) on days 1-21. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 23

Inclusion Criteria

Patient must have enrolled onto APEC1621SC and must have been given a treatment assignment to MATCH to APEC1621I based on the presence of an actionable mutation as defined in APEC1621SC
- In addition to the actionable mutations, positive Rb expression by immunohistochemistry is required for study enrollment
Patients must be >= than 12 months and =< 21 years of age at the time of study enrollment
Patients must have a body surface area >= 0.87 m^2 at enrollment
Patients must have radiographically measurable disease at the time of study enrollment; patients with neuroblastoma who do not have measurable disease but have MIBG+ evaluable disease are eligible; measurable disease in patients with CNS involvement is defined as any lesion that is at minimum 10 mm in one dimension on standard magnetic resonance imaging (MRI) or computed tomography (CT).
- Note: The following do not qualify as measurable disease:
  - Malignant fluid collections (e.g., ascites, pleural effusions)
  - Bone marrow infiltration except that detected by MIBG scan for neuroblastoma
  - Lesions only detected by nuclear medicine studies (e.g., bone, gallium or positron emission tomography [PET] scans) except as noted for neuroblastoma
  - Elevated tumor markers in plasma or cerebrospinal fluid (CSF)
  - Previously radiated lesions that have not demonstrated clear progression post radiation
  - Leptomeningeal lesions that do not meet the measurement requirements for Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 for patients =< 16 years of age; Note: Neurologic deficits in patients with CNS tumors must have been relatively stable for at least 7 days prior to study enrollment; 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
- Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive; 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
  - >= 21 days after the last dose of cytotoxic or myelosuppressive chemotherapy (42 days if prior nitrosourea)
- Anti-cancer agents not known to be myelosuppressive (e.g. not associated with reduced platelet or absolute neutrophil counts [ANC] counts): >= 7 days after the last dose of agent
- Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade =< 1
- Corticosteroids: If used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid
- 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 growth factors 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
- Interleukins, interferons and cytokines (other than hematopoietic growth factors): >= 21 days after the completion of interleukins, interferon or cytokines (other than hematopoietic growth factors)
- Stem cell infusions (with or without total body irradiation [TBI]):
  - Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem cell infusion including donor lymphocyte infusion (DLI) or boost infusion: >= 84 days after infusion and no evidence of graft versus host disease (GVHD)
  - Autologous stem cell infusion including boost infusion: >= 42 days
- Cellular therapy: >= 42 days after the completion of any type of cellular therapy (e.g. modified T cells, natural killer [NK] cells, dendritic cells, etc.)
- Radiation therapy (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 bone morrow (BM) radiation
  - Note: Radiation may not be delivered to "measurable disease" tumor site(s) being used to follow response to subprotocol treatment
- Radiopharmaceutical therapy (e.g., radiolabeled antibody, 131I-MIBG): >= 42 days after systemically administered radiopharmaceutical therapy
- Patients must not have received prior exposure to palbociclib, ribociclib, abemaciclib or any other CDK4/6 inhibitors
For patients with solid tumors without known bone marrow involvement:
- Peripheral absolute neutrophil count (ANC) >= 1000/mm^3
- Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
Patients with known bone marrow metastatic disease will be eligible for study provided they meet the blood counts (may receive transfusions provided they are not known to be refractory to red cell or platelet transfusions); these patients will not be evaluable for hematologic toxicity
Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 ml/min/1.73 m^2 or a serum creatinine based on age/gender as follows:
- Age: 1 to < 2 years; maximum serum creatinine (mg/dL): male 0.6; female 0.6
- Age: 2 to < 6 years; maximum serum creatinine (mg/dL): male 0.8; female 0.8
- Age: 6 to < 10 years; maximum serum creatinine (mg/dL): male 1; female 1
- Age: 10 to < 13 years; maximum serum creatinine (mg/dL): male 1.2; female 1.2
- Age: 13 to < 16 years; maximum serum creatinine (mg/dL): male 1.5; female 1.4
- Age: >= 16 years; maximum serum creatinine (mg/dL): male 1.7; female 1.4
Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age
Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L; (for the purpose of this study, the ULN for SGPT is 45 U/L)
Serum albumin >= 2 g/dL
Patients must be able to swallow intact capsules
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; pregnancy tests must be obtained in girls who are post-menarchal; males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method for the duration of study treatment; females study participants of child-bearing potential and their partners, should agree to use highly effective forms of contraception for at least 3 weeks after the last dose of palbociclib; male study participants should avoid fathering a child, donating sperm, and should agree to use highly effective forms of contraception for at least 3 months after the last dose of palbociclib
Concomitant medications
- Corticosteroids: Patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible; if used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid
- Investigational drugs: Patients who are currently receiving another investigational drug are not eligible
- Anti-cancer agents: Patients who are currently receiving other anti-cancer agents are not eligible
- Anti-GVHD agents post-transplant: Patients who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post bone marrow transplant are not eligible for this trial
- CYP3A4 agents: Patients who are currently receiving drugs that are strong inducers or inhibitors of CYP3A4 are not eligible; strong inducers or inhibitors of CYP3A4 should be avoided from 14 days prior to enrollment to the end of the study; Note: CYP3A4 inducing anti-epileptic drugs and dexamethasone for CNS tumors or metastases, on a stable dose, are allowed
Patients who have an uncontrolled infection are not eligible
Patients who have received a prior solid organ transplantation are not eligible
Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (palbociclib)	Laboratory Biomarker Analysis	Patients receive palbociclib PO QD on days 1-21. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.
Treatment (palbociclib)	Palbociclib	Patients receive palbociclib PO QD on days 1-21. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.
Treatment (palbociclib)	Pharmacological Study	Patients receive palbociclib PO QD on days 1-21. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Objective Response Rate	From enrollment to the end of treatment, up to 2 years	Defined as a patient who achieves a best response of partial response or complete response on the study. Confidence intervals will be constructed using the Wilson score interval method.

Secondary Outcome Measures

Name	Time	Method
Progression Free Survival (PFS)	At 6 months	PFS is defined as time from initiation of protocol treatment to disease progression, recurrence, death from any cause, or date of last contact.
Percentage of Patients Experiencing Grade 3 or Higher Adverse Events	From enrollment to 30 days after the end of treatment, up to 2 years	Assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.

Trial Locations

Locations (117): Children's Healthcare of Atlanta - Arthur M Blank Hospital
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Atlanta, Georgia, United States
Children's Hospital of Alabama
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Birmingham, Alabama, United States
Providence Alaska Medical Center
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Anchorage, Alaska, United States
Banner Children's at Desert
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Mesa, Arizona, United States
Phoenix Childrens Hospital
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Phoenix, Arizona, United States
Banner University Medical Center - Tucson
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Tucson, Arizona, United States
Arkansas Children's Hospital
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Little Rock, Arkansas, United States
Kaiser Permanente Downey Medical Center
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Downey, California, United States
City of Hope Comprehensive Cancer Center
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Duarte, California, United States
Loma Linda University Medical Center
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Loma Linda, California, United States
Miller Children's and Women's Hospital Long Beach
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Long Beach, California, United States
Children's Hospital Los Angeles
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Los Angeles, California, United States
Mattel Children's Hospital UCLA
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Los Angeles, California, United States
Valley Children's Hospital
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Madera, California, United States
UCSF Benioff Children's Hospital Oakland
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Oakland, California, United States
Kaiser Permanente-Oakland
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Oakland, California, United States
Children's Hospital of Orange County
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Orange, California, United States
Lucile Packard Children's Hospital Stanford University
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Palo Alto, California, United States
University of California Davis Comprehensive Cancer Center
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Sacramento, California, United States
UCSF Medical Center-Mission Bay
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San Francisco, California, United States
Children's Hospital Colorado
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Aurora, Colorado, United States
Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center
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Denver, Colorado, United States
Alfred I duPont Hospital for Children
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Wilmington, Delaware, United States
MedStar Georgetown University Hospital
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Washington, District of Columbia, United States
Children's National Medical Center
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Washington, District of Columbia, United States
Broward Health Medical Center
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Fort Lauderdale, Florida, United States
University of Florida Health Science Center - Gainesville
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Gainesville, Florida, United States
Nemours Children's Clinic-Jacksonville
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Jacksonville, Florida, United States
University of Miami Miller School of Medicine-Sylvester Cancer Center
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Miami, Florida, United States
Nicklaus Children's Hospital
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Miami, Florida, United States
AdventHealth Orlando
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Orlando, Florida, United States
Arnold Palmer Hospital for Children
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Orlando, Florida, United States
Nemours Children's Hospital
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Orlando, Florida, United States
Johns Hopkins All Children's Hospital
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Saint Petersburg, Florida, United States
Saint Joseph's Hospital/Children's Hospital-Tampa
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Tampa, Florida, United States
Kapiolani Medical Center for Women and Children
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Honolulu, Hawaii, United States
Saint Luke's Cancer Institute - Boise
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Boise, Idaho, United States
University of Chicago Comprehensive Cancer Center
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Chicago, Illinois, United States
Saint Jude Midwest Affiliate
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Peoria, Illinois, United States
Southern Illinois University School of Medicine
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Springfield, Illinois, United States
Riley Hospital for Children
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Indianapolis, Indiana, United States
Blank Children's Hospital
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Des Moines, Iowa, United States
University of Iowa/Holden Comprehensive Cancer Center
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Iowa City, Iowa, United States
University of Kentucky/Markey Cancer Center
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Lexington, Kentucky, United States
Children's Hospital New Orleans
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New Orleans, Louisiana, United States
Ochsner Medical Center Jefferson
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New Orleans, Louisiana, United States
Eastern Maine Medical Center
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Bangor, Maine, United States
Sinai Hospital of Baltimore
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Baltimore, Maryland, United States
Johns Hopkins University/Sidney Kimmel Cancer Center
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Baltimore, Maryland, United States
Massachusetts General Hospital Cancer Center
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Boston, Massachusetts, United States
Dana-Farber Cancer Institute
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Boston, Massachusetts, United States
C S Mott Children's Hospital
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Ann Arbor, Michigan, United States
Corewell Health Grand Rapids Hospitals - Helen DeVos Children's Hospital
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Grand Rapids, Michigan, United States
Bronson Methodist Hospital
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Kalamazoo, Michigan, United States
Children's Hospitals and Clinics of Minnesota - Minneapolis
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Minneapolis, Minnesota, United States
University of Minnesota/Masonic Cancer Center
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Minneapolis, Minnesota, United States
University of Mississippi Medical Center
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Jackson, Mississippi, United States
Children's Mercy Hospitals and Clinics
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Kansas City, Missouri, United States
Cardinal Glennon Children's Medical Center
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Saint Louis, Missouri, United States
Washington University School of Medicine
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Saint Louis, Missouri, United States
Mercy Hospital Saint Louis
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Saint Louis, Missouri, United States
Children's Hospital and Medical Center of Omaha
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Omaha, Nebraska, United States
University of Nebraska Medical Center
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Omaha, Nebraska, United States
Hackensack University Medical Center
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Hackensack, New Jersey, United States
Morristown Medical Center
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Morristown, New Jersey, United States
Saint Peter's University Hospital
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New Brunswick, New Jersey, United States
Albany Medical Center
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Albany, New York, United States
Roswell Park Cancer Institute
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Buffalo, New York, United States
The Steven and Alexandra Cohen Children's Medical Center of New York
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New Hyde Park, New York, United States
NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
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New York, New York, United States
Memorial Sloan Kettering Cancer Center
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New York, New York, United States
NYP/Weill Cornell Medical Center
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New York, New York, United States
University of Rochester
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Rochester, New York, United States
State University of New York Upstate Medical University
🇺🇸
Syracuse, New York, United States
Mission Hospital
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Asheville, North Carolina, United States
Carolinas Medical Center/Levine Cancer Institute
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Charlotte, North Carolina, United States
Duke University Medical Center
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Durham, North Carolina, United States
Sanford Broadway Medical Center
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Fargo, North Dakota, United States
Cincinnati Children's Hospital Medical Center
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Cincinnati, Ohio, United States
Rainbow Babies and Childrens Hospital
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Cleveland, Ohio, United States
Nationwide Children's Hospital
🇺🇸
Columbus, Ohio, United States
Dayton Children's Hospital
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Dayton, Ohio, United States
ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital
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Toledo, Ohio, United States
University of Oklahoma Health Sciences Center
🇺🇸
Oklahoma City, Oklahoma, United States
Legacy Emanuel Children's Hospital
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Portland, Oregon, United States
Oregon Health and Science University
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Portland, Oregon, United States
Geisinger Medical Center
🇺🇸
Danville, Pennsylvania, United States
Children's Hospital of Philadelphia
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Philadelphia, Pennsylvania, United States
Children's Hospital of Pittsburgh of UPMC
🇺🇸
Pittsburgh, Pennsylvania, United States
Prisma Health Richland Hospital
🇺🇸
Columbia, South Carolina, United States
BI-LO Charities Children's Cancer Center
🇺🇸
Greenville, South Carolina, United States
Sanford USD Medical Center - Sioux Falls
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Sioux Falls, South Dakota, United States
East Tennessee Childrens Hospital
🇺🇸
Knoxville, Tennessee, United States
Saint Jude Children's Research Hospital
🇺🇸
Memphis, Tennessee, United States
Vanderbilt University/Ingram Cancer Center
🇺🇸
Nashville, Tennessee, United States
Dell Children's Medical Center of Central Texas
🇺🇸
Austin, Texas, United States
Driscoll Children's Hospital
🇺🇸
Corpus Christi, Texas, United States
Medical City Dallas Hospital
🇺🇸
Dallas, Texas, United States
UT Southwestern/Simmons Cancer Center-Dallas
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Dallas, Texas, United States
Cook Children's Medical Center
🇺🇸
Fort Worth, Texas, United States
Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
🇺🇸
Houston, Texas, United States
M D Anderson Cancer Center
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Houston, Texas, United States
Covenant Children's Hospital
🇺🇸
Lubbock, Texas, United States
Children's Hospital of San Antonio
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San Antonio, Texas, United States
Methodist Children's Hospital of South Texas
🇺🇸
San Antonio, Texas, United States
Scott and White Memorial Hospital
🇺🇸
Temple, Texas, United States
Primary Children's Hospital
🇺🇸
Salt Lake City, Utah, United States
University of Vermont and State Agricultural College
🇺🇸
Burlington, Vermont, United States
Children's Hospital of The King's Daughters
🇺🇸
Norfolk, Virginia, United States
Virginia Commonwealth University/Massey Cancer Center
🇺🇸
Richmond, Virginia, United States
Seattle Children's Hospital
🇺🇸
Seattle, Washington, United States
Providence Sacred Heart Medical Center and Children's Hospital
🇺🇸
Spokane, Washington, United States
Madigan Army Medical Center
🇺🇸
Tacoma, Washington, United States
University of Wisconsin Carbone Cancer Center - University Hospital
🇺🇸
Madison, Wisconsin, United States
Children's Hospital of Wisconsin
🇺🇸
Milwaukee, Wisconsin, United States
San Jorge Children's Hospital
🇵🇷
San Juan, Puerto Rico
University Pediatric Hospital
🇵🇷
San Juan, Puerto Rico