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Study Of Palbociclib Combined With Chemotherapy In Pediatric Patients With Recurrent/Refractory Solid Tumors

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ClinicalTrials.gov Identifier: NCT03709680
Recruitment Status : Recruiting
First Posted : October 17, 2018
Last Update Posted : June 10, 2021
Sponsor:
Information provided by (Responsible Party):
Pfizer

Brief Summary:
This study will evaluate palbociclib in combination with chemotherapy (temozolomide with irinotecan and topotecan with cyclophosphamide) in children, adolescents and young adults with recurrent or refractory solid tumors. The main purpose of this study is to evaluate the safety of palbociclib in combination with chemotherapy in order to estimate the maximum tolerated dose. Pharmacokinetics and efficacy of palbociclib in combination with chemotherapy will be evaluated.

Condition or disease Intervention/treatment Phase
Solid Tumors Ewing Sarcoma Rhabdoid Tumor Rhabdomyosarcoma Neuroblastoma Medulloblastoma Diffuse Intrinsic Pontine Glioma Drug: Palbociclib Drug: Temozolomide Drug: Irinotecan Drug: Topotecan Drug: Cyclophosphamide Phase 1

Expanded Access : Pfizer has indicated that access to an investigational treatment associated with this study is available outside the clinical trial.  

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 133 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:

The palbociclib plus irinotecan and temozolomide combination part of the study will comprise of a dose escalation cohort (following a rolling 6 design), a dose expansion cohort, EWS tumor specific cohort and if applicable, other solid tumor-specific cohorts.

The palbociclib plus topotecan and cyclophosphamide will comprise of a dose determination cohort(following a modified rolling 6 design), a dose expansion cohort, and if applicable, other solid tumor-specific cohorts.

Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: PHASE 1 STUDY TO EVALUATE THE SAFETY AND PHARMACOKINETICS OF PALBOCICLIB (IBRANCE(REGISTERED)) IN COMBINATION WITH IRINOTECAN AND TEMOZOLOMIDE AND IN COMBINATION WITH TOPOTECAN AND CYCLOPHOSPHAMIDE IN PEDIATRIC PATIENTS WITH RECURRENT OR REFRACTORY SOLID TUMORS
Actual Study Start Date : May 24, 2019
Estimated Primary Completion Date : November 29, 2021
Estimated Study Completion Date : January 13, 2025


Arm Intervention/treatment
Experimental: Single Arm
Palbociclib in combination with temozolomide and irinotecan Palbociclib in combination with topotecan and cyclophosphamide
Drug: Palbociclib
Administered (oral) at 55 mg/m2, 75 mg/m2, or 40 mg/m2, or 95 mg/m2 or 115 mg/m2 on days 1-14 of a 21-day cycle
Other Name: Ibrance

Drug: Temozolomide
Administered at 100 mg/m2 (oral or intravenous), on days 1-5 of a 21-day cycle

Drug: Irinotecan
Administered at 50 mg/m2 (intravenous), on days 1-5 of a 21-day cycle

Drug: Topotecan
Administered at 0.75 mg/m2 (intravenous), on days 1-5 of a 21-day cycle

Drug: Cyclophosphamide
Administered at 250 mg/m2 (intravenous), on days 1-5 of a 21-day cycle




Primary Outcome Measures :
  1. Dose Escalation Part and Dose Determination Part: Frequency of dose-limiting toxicities (DLT) [ Time Frame: First cycle (cycle length is approximately 21 days) ]
    For Dose Escalation/Determination Part: DLT defined as any of the following events occurring during the first treatment cycle and considered at least possibly-related to study medication:Grade 4 neutropenia lasting greater than 7 days;Grade 4 thrombocytopenia lasting greater than 7 days or need for platelet transfusion for a platelet count of < 20,000 per cubic millimeters twice within a 7-day period;greater than 14-day delay in the start of a subsequent course because of neutropenia or thrombocytopenia;Grade 3 or greater non-hematologic toxicities despite optimal treatment;any Grade 2 or greater non-hematologic toxicity requiring discontinuation or interruption of palbociclib for 7 or more consecutive days during the first cycle or any grade non-hematologic toxicity that delays the start of Cycle 2 by more than 14 days;clinically significant non-hematologic laboratory test abnormality Grade 3 or greater not resolving to Grade 1 or baseline within 7 days.

  2. Dose Expansion Parts: Frequency of adverse events [ Time Frame: At least 28 days after last dose ]
    For Dose Expansion and Tumor-Specific Expansion Parts: Adverse events to be reported during treatment and for at least 28 days after last dose.

  3. Dose Expansion Parts: Percentage of Participants With Complete Response or Partial Response [ Time Frame: Through the end of treatment (up to at least 28 days after last dose) ]
    For Dose Expansion and Tumor-Specific Expansion Parts: patients with confirmed Complete Response or Partial Response per Response Evaluation Criteria in Solid Tumors (RECIST, v.1.1) or modified Response Assessment in Neuro-Oncology (RANO) for central nervous system malignancies, or International Neuroblastoma Response Criteria (INRC) for neuroblastoma, during study treatment, assessed approximately every 2 to 4 cycles (each cycle is approximately 21 days).


Secondary Outcome Measures :
  1. Frequency of adverse events [ Time Frame: At least 28 days after last dose ]
    Adverse events to be reported during treatment and for at least 28 days after last dose.

  2. Percentage of participants with laboratory abnormalities [ Time Frame: At least 28 days after last dose ]
    Magnesium, Calcium, Creatinine, Albumin, Alanine aminotransferase, Aspartate aminotransferase, Glucose, Phosphorus, Total Bilirubin, Blood urea nitrogen, Alkaline phosphatase, Sodium, Potassium, Chloride, Platelet Count, White Blood Cell Count (differential), hemoglobin, INR or prothrombin Time, HbA1c

  3. Number of Participants With Clinically Significant Treatment-emergent Electrocardiogram (ECG) Findings [ Time Frame: At least 28 days after last dose ]
    Clinically significant ECG findings included: corrected QT (QTc) > 450 ms, QTc >500 ms, change in QTc between 30 and 60 ms, change in QTc greater than or equal to 60 ms.

  4. Number of Participants With Clinically Significant Change From Baseline in Vital Signs [ Time Frame: At least 28 days after last dose ]
    systolic and diastolic blood pressure, pulse

  5. Percentage of Participants With Complete Response or Partial Response [ Time Frame: Through the end of treatment (up to at least 28 days after last dose) ]
    Patients with confirmed Complete Response or Partial Response per Response Evaluation Criteria in Solid Tumors (RECIST, v.1.1) or modified Response Assessment in Neuro-Oncology (RANO) for central nervous system malignancies, or International Neuroblastoma Response Criteria (INRC) for neuroblastoma, during study treatment, assessed approximately every 2 to 4 cycles (each cycle is approximately 21 days).

  6. Duration of response (DoR) for Participants Who Achieved Complete Response or Partial Response [ Time Frame: Up to 2 years ]
    DoR defined as time from date of first response (Complete Response or Partial Response) in responders to date of progression or death

  7. Progression Free Survival (PFS) [ Time Frame: Up to 2 years ]
    PFS defined as time from date of enrollment to earliest date of the death or progressive disease

  8. Overall Survival (OS) [ Time Frame: Up to 2 years ]
    OS defined as the time from enrollment to date of death due to any cause.

  9. Palbociclib Pharmacokinetics, Maximum observed plasma concentration during a dosing interval at steady state (Css, max) [ Time Frame: PK sampling at time points during Cycle 1 (day 2, 5, 6, 14) and Cycle 2 (day 5 and 14). Each cycle is 21 days. ]
    Multiple Dose (assuming steady state is achieved), as data permit

  10. Palbociclib Pharmacokinetics, Maximum plasma concentration time (Tmax) [ Time Frame: PK sampling at time points during Cycle 1 (day 2, 5, 6, 14) and Cycle 2 (day 5 and 14). Each cycle is 21 days. ]
    Multiple Dose (assuming steady state is achieved), as data permit

  11. Palbociclib Pharmacokinetics, Area under the concentration-time curve during a dosing interval at steady state (AUCss,t) [ Time Frame: PK sampling at time points during Cycle 1 (day 2,5, 6,14) and Cycle 2 (day 5 and 14). Each cycle is 21 days. ]
    Multiple Dose (assuming steady state is achieved), as data permit

  12. Palbociclib Pharmacokinetics, Measured concentration at the end of a dosing interval at steady state (taken directly before next administration) (Css,trough) [ Time Frame: PK sampling at time points during Cycle 1 (day 2, 5, 6, 14) and Cycle 2 (day 5 and 14). Each cycle is 21 days. ]
    Multiple Dose (assuming steady state is achieved), as data permit

  13. Palbociclib Pharmacokinetics, Oral plasma clearance (CL/F) [ Time Frame: PK sampling at time points during Cycle 1 (day 2, 5, 6, 14) and Cycle 2 (day 5 and 14). Each cycle is 21 days. ]
    Multiple Dose (assuming steady state is achieved), as data permit

  14. Temozolomide Pharmacokinetics, Maximum observed plasma concentration during a dosing interval at steady state (Css, max) [ Time Frame: PK sampling at time points during Cycle 1 (day 5) and Cycle 2 (day 5). Each cycle is 21 days. ]
    Multiple Dose (assuming steady state is achieved), as data permit

  15. Temozolomide Pharmacokinetics, Maximum plasma concentration time (Tmax) [ Time Frame: PK sampling at time points during Cycle 1 (day 5) and Cycle 2 (day 5). Each cycle is 21 days. ]
    Multiple Dose (assuming steady state is achieved), as data permit

  16. Temozolomide Pharmacokinetics, Area under the concentration-time curve during a dosing interval at steady state (AUCss,t) [ Time Frame: PK sampling at time points during Cycle 1 (day 5) and Cycle 2 (day 5). Each cycle is 21 days. ]
    Multiple Dose (assuming steady state is achieved), as data permit

  17. Temozolomide Pharmacokinetics, Measured concentration at the end of a dosing interval at steady state (taken directly before next administration) (Css,trough) [ Time Frame: PK sampling at time points during Cycle 1 (day 5) and Cycle 2 (day 5). Each cycle is 21 days. ]
    Multiple Dose (assuming steady state is achieved), as data permit

  18. Temozolomide Pharmacokinetics, Oral plasma clearance (CL/F) [ Time Frame: PK sampling at time points during Cycle 1 (day 5) and Cycle 2 (day 5). Each cycle is 21 days. ]
    Multiple Dose (assuming steady state is achieved), as data permit

  19. Irinotecan (and active metabolites) Pharmacokinetics, Maximum observed plasma concentration during a dosing interval at steady state (Css, max) [ Time Frame: PK sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days. ]
    Multiple Dose (assuming steady state is achieved), as data permit

  20. Irinotecan (and active metabolites) Pharmacokinetics, Maximum plasma concentration time (Tmax) [ Time Frame: PK sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days. ]
    Multiple Dose (assuming steady state is achieved), as data permit

  21. Irinotecan (and active metabolites) Pharmacokinetics, Area under the concentration-time curve during a dosing interval at steady state (AUCss,t) [ Time Frame: PK sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days. ]
    Multiple Dose (assuming steady state is achieved), as data permit

  22. Irinotecan (and active metabolites), Measured concentration at the end of a dosing interval at steady state (taken directly before next administration) (Css,trough) [ Time Frame: PK sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days. ]
    Multiple Dose (assuming steady state is achieved), as data permit

  23. Irinotecan (and active metabolites) Pharmacokinetics, Oral plasma clearance (CL/F) [ Time Frame: PK sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days. ]
    Multiple Dose (assuming steady state is achieved), as data permit

  24. Topotecan (and active metabolites) Pharmacokinetics, Oral plasma clearance (CL/F) [ Time Frame: PK sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days. ]
    Multiple Dose (assuming steady state is achieved), as data permit

  25. Topotecan (and active metabolites), Measured concentration at the end of a dosing interval at steady state (taken directly before next administration) (Css,trough) [ Time Frame: PK sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days. ]
    Multiple Dose (assuming steady state is achieved), as data permit

  26. Topotecan (and active metabolites) Pharmacokinetics, Area under the concentration-time curve during a dosing interval at steady state (AUCss,t) [ Time Frame: PK sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days. ]
    Multiple Dose (assuming steady state is achieved), as data permit

  27. Topotecan (and active metabolites) Pharmacokinetics, Maximum plasma concentration time (Tmax) [ Time Frame: PK sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days. ]
    Multiple Dose (assuming steady state is achieved), as data permit

  28. Topotecan (and active metabolites) Pharmacokinetics, Maximum observed plasma concentration during a dosing interval at steady state (Css, max) [ Time Frame: PK sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days. ]
    Multiple Dose (assuming steady state is achieved), as data permit

  29. Cyclophosphamide Pharmacokinetics, Oral plasma clearance (CL/F) [ Time Frame: PK sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days. ]
    Multiple Dose (assuming steady state is achieved), as data permit

  30. Cyclophosphamide Pharmacokinetics, Maximum observed plasma concentration during a dosing interval at steady state (Css, max) [ Time Frame: PK sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days. ]
    Multiple Dose (assuming steady state is achieved), as data permit

  31. Cyclophosphamide Pharmacokinetics, Maximum plasma concentration time (Tmax) [ Time Frame: PK sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days. ]
    Multiple Dose (assuming steady state is achieved), as data permit

  32. Cyclophosphamide Pharmacokinetics, Area under the concentration-time curve during a dosing interval at steady state (AUCss,t) [ Time Frame: PK sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days. ]
    Multiple Dose (assuming steady state is achieved), as data permit

  33. Cyclophosphamide Pharmacokinetics, Measured concentration at the end of a dosing interval at steady state (taken directly before next administration) (Css,trough) [ Time Frame: PK sampling at time points during Cycle 1 (day 2, 5 and 6) and Cycle 2 (day 5). Each cycle is 21 days. ]
    Multiple Dose (assuming steady state is achieved), as data permit



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:   2 Years to 20 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion:

  1. Histologically confirmed relapsed or refractory solid tumor as follows:

    • For dose escalation and dose determination parts: Histologically confirmed relapsed or refractory solid tumor (including CNS tumors but not lymphomas). Patients with Diffuse Intrinsic Pontine Glioma do not require histological only radiographic confirmed relapse to enroll.
    • For dose expansion and tumor specific cohorts: Histologically confirmed relapsed or refractory solid tumor including but not limited to EWS, rhabdoid tumor, rhabdomyosarcoma, neuroblastoma, and medulloblastoma. Patients with Diffuse Intrinsic Pontine Glioma do not require histological only radiographic confirmed relapse to enroll. EWS is not eligible for TOPO and CTX tumor-specific cohorts.
  2. Age ≥2 and <21 years at the time of study entry.
  3. Lansky performance status ≥50% for patients ≤16 years of age, or Eastern Cooperative Oncology Group (ECOG) 0, 1 or 2 for patients >16 years of age.
  4. Adequate bone marrow function.

    • Absolute neutrophil count ≥1000/mm3;
    • Platelet count ≥100,000/mm3 (transfusion independent);
    • Hemoglobin ≥8.5 g/dL (transfusion allowed).
  5. Adequate renal function: Serum creatinine level based on age/gender must within protocol specified limits.
  6. Adequate liver function, including:

    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT)

      ≤2.5 × upper limit of normal (ULN) or ≤5 × ULN for age, if attributable to disease involvement of the liver;

    • Total bilirubin ≤1.5 × ULN for age.
  7. Measurable disease as defined by RECIST version 1.1 or modified RANO criteria for CNS disease or INRC for neuroblastoma.
  8. Recovered to CTCAE Grade ≤1, or to baseline, from any non-hematological acute toxicities of prior surgery, chemotherapy, immunotherapy, radiotherapy, differentiation therapy or biologic therapy, with the exception of alopecia.
  9. Serum/urine pregnancy test (for all girls ≥8 years of age) negative at screening and at the baseline visit.
  10. Evidence of a personally signed and dated informed consent document indicating that the patient or a legally acceptable representative/parent(s)/legal guardian of minors, has been informed of all pertinent aspects of the study. Minor study patients also must provide age appropriate assent according to the local guidelines, where applicable.
  11. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other procedures.

Exclusion:

  1. For palbociclib with IRN and TMZ combination, prior treatment with a CDK4/6 inhibitor or progression while on treatment with an IRN-containing regimen that includes TMZ. Patients who have received the combination of IRN and TMZ and did not progress while on these medications are eligible. For patients enrolling in the palbociclib with TOPO and CTX combination, prior treatment with a CDK4/6 inhibitor or progression while on treatment with a TOPO-containing regimen that includes CTX. Patients who have received the combination of TOPO and CTX and did not progress while on these medications are eligible.
  2. Prior intolerability to IRN and/or TMZ, for palbociclib with IRN and TMZ combination and prior intolerability to TOPO and/or CTX for palbociclib with TOPO and CTX combination.
  3. Use of strong cytochrome P450 (CYP) 3A inhibitors or inducers. Patients who are receiving strong uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1) inhibitors within 12 days of Cycle 1 Day 1 (C1D1) are not eligible for the palbociclib with IRN and TMZ combination. Patients who are receiving strong UGT1A1 inhibitors within 12 days of C1D1 are eligible for the palbociclib with TOPO and CTX combination (See Section 5.7.1 for list of products.)
  4. Prior growth factors (including filgrastim) within 7 days before study entry or PEG-filgrastim within 14 days before study entry.
  5. Radiation therapy within 14 days before study entry.
  6. Systemic anti cancer therapy within 2 weeks prior to study entry and 6 weeks for nitrosoureas.
  7. Previous high dose chemotherapy requiring stem cell rescue within 90 days or persistent AE >Grade 1.
  8. Prior irradiation to >50% of the bone marrow (see Appendix 9).
  9. Participation in other studies involving investigational drug(s) within 2 weeks or 5 half lives, whichever is longer, prior to study entry.
  10. Major surgery within 4 weeks prior to study entry. Surgical biopsies or central line placement are not considered major surgeries.
  11. Known or suspected hypersensitivity to palbociclib, IRN and/or TMZ.
  12. Patients with known symptomatic brain tumors or brain metastases and require steroids, unless they have been on a stable or on a decreasing steroid dose for >14 days.
  13. Patients with previously diagnosed brain metastases are eligible if they have completed their prior treatment and have recovered from the acute effects of radiation therapy or surgery prior to study entry for these metastases for at least 14 days post radiation and 4 weeks post-surgery and are neurologically stable.
  14. Hereditary bone marrow failure disorder.
  15. QTc >470 msec.
  16. History of clinically significant or uncontrolled cardiac disease, including:

    • History of or active congestive heart failure; if patient had congestive heart failure resolve and >1 year from resolution, patient will be considered eligible;
    • Clinically significant ventricular arrhythmia (such as ventricular tachycardia, ventricular fibrillation or Torsades de Pointes);
    • Diagnosed or suspected congenital or acquired prolonged QT syndrome;
    • Need for medications known to prolong the QT interval;
    • Uncorrected hypomagnesemia or hypokalemia because of potential effects on the QT interval;
    • Left ventricular ejection fraction <50% or shortening fraction <28%.
  17. Recent or ongoing clinically significant gastrointestinal disorder that may interfere with absorption of orally administered drugs (eg, gastrectomy).
  18. Evidence of serious active or uncontrolled bacterial, fungal or viral infection or known history of hepatitis B virus, hepatitis C virus, or human immunodeficiency virus infection or acquired immunodeficiency syndrome-related illness.
  19. Other severe acute or chronic medical or laboratory test abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results, and in the judgment of the Investigator, would make the patient inappropriate for entry into this study.
  20. Investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or patients who are Pfizer employees, including their family members, directly involved in the conduct of the study.
  21. Fertile male patients and female patients of childbearing potential who are unwilling or unable to use a highly effective method of contraception as outlined in this protocol for the duration of the study and for at least 90 after the last dose of investigational product.

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): NCT03709680


Contacts
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Contact: Pfizer CT.gov Call Center 1-800-718-1021 ClinicalTrials.gov_Inquiries@pfizer.com

Locations
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Sponsors and Collaborators
Pfizer
Investigators
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Study Director: Pfizer CT.gov Call Center Pfizer
Additional Information:
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Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT03709680    
Other Study ID Numbers: A5481092
First Posted: October 17, 2018    Key Record Dates
Last Update Posted: June 10, 2021
Last Verified: June 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Pfizer:
Solid tumor, EWS, RMS, NBL, Brain
tumor
Additional relevant MeSH terms:
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Rhabdomyosarcoma
Neoplasms
Neuroblastoma
Sarcoma, Ewing
Medulloblastoma
Rhabdoid Tumor
Sarcoma
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neuroectodermal Tumors, Primitive, Peripheral
Neuroectodermal Tumors, Primitive
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Myosarcoma
Neoplasms, Muscle Tissue
Osteosarcoma
Neoplasms, Bone Tissue
Neoplasms, Connective Tissue
Glioma
Neoplasms, Complex and Mixed
Cyclophosphamide
Temozolomide
Irinotecan
Topotecan
Palbociclib
Immunosuppressive Agents
Immunologic Factors