MC# 20-18 - An Open-Label, Multicenter, Phase II Basket Study to Evaluate the Efficacy and Safety of Lenvatinib (14 mg/m2) in Children, Adolescents, and Young Adults with Relapsed or Refractory Solid Malignancies (Pediatric Solid Tumor Basket Trial)

  • Agent(s): Lenvatinib
  • Disease Type(s): Solid Tumor
  • Phase(s): II
  • Drug Classification(s): Small Molecule, Targeted Therapy
  • Molecular Target(s): MET, VEGFR, RTK

Mechanism of Action

Lenvatinib (E7080) is an orally available potent inhibitor of the split-kinase family of transmembrane growth factor receptors including Flt-1/VEGFR-1 and KDR/VEGFR-2.


In this study, the sponsor and investigators want to learn:

  • About the safety and tolerability of lenvatinib
  • How proteins that indicate the status of your disease are affected with use of lenvatinib
  • If lenvatinib prevents or delays tumor growth or shrinks existing tumors
  • How much of lenvatinib is absorbed into the blood and how fast it is removed
Inclusion Criteria

Type of Participant and Disease Characteristics

  1. Has histologically or cytologically documented relapsed, or refractory pediatric solid malignancy excluding osteosarcoma.  Participants with diffuse intrinsic pontine glioma, optic pathway glioma, or pineal tumors with elevated tumor markers (AFP, ß-hCG, or hCG]) do not require histological or cytological confirmation of diagnosis.  Participants with diffuse intrinsic pontine glioma are not eligible for the HGG cohort and should only be enrolled in the other solid tumors cohort.
  2. Has measurable disease as defined by RECIST 1.1 or RANO for HGG, meeting the criteria below:
    • All tumor types except HGG and neuroblastoma: At least 1 lesion measuring ≥1.0 cm in the longest diameter for a non-lymph node or ≥1.5 cm in the short-axis diameter for a lymph node that is reproducibly measurable on CT or MRI scans
    • HGG: At least 1 contrast-enhancing lesion with clearly defined margins on T1-weighted MRI scan, measuring ≥1.0 cm in 2 perpendicular diameters, and visible on at least 2 axial slices (preferably no more than 5 mm apart with 0 mm gap)
    • Participants with neuroblastoma who do not have measurable disease per RECIST 1.1 but have MIBG-positive evaluable disease may be enrolled
    • Tumor lesions situated in a previously irradiated area or in an area subjected to other locoregional therapy are considered measurable only if progression has been observed in such lesions since the completion of therapy
  3. Has a performance status as defined below:
    • Lansky Play Score ≥50 for participants up to and including 16 years of age
    • KPS ≥50 for participants >16 years of age
    • Neurologic deficits in participants with primary CNS tumors must have been stable for at least 7 days prior to study enrollment.  Participants 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.
  4. Demonstrate adequate organ function as defined below:


Laboratory Value


For participants without bone marrow involvement






≥8.0 g/dL (a hemoglobin of <8.0 g/dL is acceptable if it is corrected by growth factor or transfusion before C1D1)

For participants with known bone marrow involvement


≥800/µL and leucocyte count ≥1×109/L


≥75,000/µL  (with no platelet transfusion for at least 7 days prior to enrollment)


May receive transfusions provided they are not known to be refractory to red cell transfusions.


Creatinine by age/gendera











Measured or calculatedb creatinine clearance



Maximum Serum Creatinine (mg/dL)






2 to <6 years




6 to <10 years




10 to <13 years




13 to <16 years




≥16 years





≥70 mL/min/1.73 m2


Total bilirubin

≤1.5 ×ULN for age, except for unconjugated hyperbilirubinemia of Gilbert’s syndrome


ALT and AST ≤3 × ULN (in the case of liver metastases ≤5 × ULN)




≤1.5 (participants on anticoagulant therapy must remain within the therapeutic INR range)

ALT=alanine aminotransferase; ANC=absolute neutrophil count; AST=aspartate aminotransferase; GFR=glomerular filtration rate; INR=international normalized ratio; ULN=upper limit of normal.

a. The threshold creatinine values in this table were derived from the Schwartz formula for estimating GFR utilizing child length and stature data published by the CDC.

b. Creatinine clearance should be calculated per institutional standards (see Appendix 7 for country-specific requirements).

  1. Urine dipstick <2+ for proteinuria.  Participants who have ≥2+ proteinuria on dipstick urinalysis should undergo a spot P/C ratio that should be Grade <2 per CTCAE v5.0, and if possible, perform a 24-hour urine collection (children and adolescents ≤12 years of age must have ≤500 mg of protein/24 hours and participants >12 years of age must have ≤1 g of protein/24 hours).
  2. No clinical evidence of nephrotic syndrome
  3. Has adequate BP control with or without antihypertensive medications, defined as:
    • BP < the 95th percentile for sex, age, and height/length (≤150/90 mm Hg for participants aged 18 to 21 years) at Screening (as per NHLBI guidelines; Section 10.11-10.12) and no change in antihypertensive medications within 1 week prior to Cycle 1 Day 1
  4. Has adequate cardiac function:
    • Adequate cardiac function as evidenced by left ventricular shortening fraction of ≥27% by echocardiogram or LVEF ≥50% at C1D1 prior to allocation as determined by echocardiography or MUGA scan
    • QT interval corrected for heart rate using Fridericia’s formula (QTcF) ≤480 msec
  5. Has adequate neurologic function:
    • Participants with seizure disorder may be enrolled if on anticonvulsants and seizure disorder is well controlled
  6. Participant must have fully recovered to CTCAE v5.0 Grade ≤1 (except for alopecia, ototoxicity, and Grade ≤2 peripheral neuropathy) from the acute toxic effects of all prior anticancer therapy and must meet the following minimum duration from prior anticancer-directed therapy prior to enrollment.  If after the required timeframe, the numerical eligibility criteria are met, eg, blood count criteria, the participant is considered to have recovered adequately.
    1. Cytotoxic chemotherapy or other chemotherapy known to be myelosuppressive: ≥21 days after the last dose of cytotoxic or myelosuppressive chemotherapy (42 days if prior nitrosourea)
    2. Anticancer agents not known to be myelosuppressive (eg, not associated with reduced platelet or absolute neutrophil counts): ≥7 days after the last dose of agent
    3. Monoclonal antibodies: ≥21 days or 3 half-lives (whichever is shorter) of the antibody must have elapsed after the last dose of a monoclonal antibody (including checkpoint inhibitors; Appendix 14).  Toxicity related to prior antibody therapy must be recovered to Grade ≤1.
    4. Corticosteroids: If used to modify immune AEs related to prior therapy, ≥14 days must have elapsed since last dose of corticosteroid.  Participants 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.
    5. Hematopoietic growth factors: ≥14 days after the last dose of a long-acting growth factor (eg, NEULASTA®) or 7 days for short-acting growth factor.  For agents that have known AEs occurring beyond 7 days after administration, this period must be extended beyond the time during which AEs are known to occur.
    6. Interleukins, interferons, and cytokines (other than hematopoietic growth factors): ≥21 days after the completion of interleukins, interferons, or cytokines (other than hematopoietic growth factors)
    7. Stem cell infusions (with or without total body irradiation):
      • Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem cell infusion including donor leukocytes infusion or boost infusion: ≥84 days after infusion and no evidence of graft versus host disease
      • Autologous stem cell infusion including boost infusion: ≥42 days
    8. Cellular Therapy: ≥42 days after the completion of any type of cellular therapy (eg, modified T cells, natural killer cells, dendritic cells, etc)
    9. Radiotherapy (XRT)/External Beam Irradiation including Protons: ≥14 days after local XRT; ≥150 days after total body irradiation, craniospinal XRT, or if radiation to ≥50% of the pelvis; ≥42 days if other substantial bone marrow radiation
    10. Radiopharmaceutical therapy (eg, 131I-MIBG): ≥42 days after systemically administered radiopharmaceutical therapy
    11. VEGF/VEGFR-targeted therapies:
      • Must not have received prior exposure to lenvatinib
      • No more than 2 prior VEGF/VEGFR-targeted therapies


  1. Male or female ≥2 years to ≤ 18 years of age (≤21 years for EWS/pPNET), on the day the main informed consent/assent is signed

Male Participants

  1. Male participants are eligible to participate if they agree to the following during the intervention period and for at least 30 days after the last dose of study intervention:
    • Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent OR
    • Must agree to use contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause [Appendix 5]) as detailed below:
      • Agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP who is not currently pregnant.  Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse or use a male condom during each episode of penile-vaginal penetration.

Female Participants

Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.

  1. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
    • Is not a WOCBP OR
    • Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis), as described in Appendix [5] during the intervention period and for at least 30 days post lenvatinib
    • A WOCBP must have a negative highly sensitive pregnancy test ([urine or serum] as required by local regulations) within 24 hours before the first dose of study intervention
    • If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive
    • Additional requirements for pregnancy testing during and after study intervention are located in Appendix 2
    • The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy

Informed Consent/ Assent

  1. Be willing and able to provide (and/or their parents or legal guardians) written informed consent/assent for the study.  Written informed consent required from participants ≥18 years.
  2. Willing and able to comply with the protocol, scheduled follow-up, and management of toxicity as judged by the investigator
Exclusion Criteria

Medical Conditions

  1. Is a WOCBP who has a positive urine pregnancy test within 24 hours before the first dose of study intervention (see Appendix 5).  If the urine test cannot be confirmed as negative, a serum pregnancy test is required.  In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
  2. Has had major surgery within 3 weeks prior to C1D1.  Note: Adequate wound healing after major surgery must be assessed clinically, independent of time elapsed for eligibility.
  3. Has GI bleeding or active hemoptysis (bright red blood of at least half teaspoon) within 21 days prior to enrollment
  4. Has CNS tumors with a history of symptomatic tumor hemorrhage
  5. Has evidence of new intracranial hemorrhage of more than punctate size on MRI assessment obtained within 28 days prior to study enrollment
  6. Has radiographic evidence of encasement or invasion of a major blood vessel or of intratumoral cavitation.  Note: The degree of proximity to major blood vessels should be considered for exclusion because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis after lenvatinib therapy.
  7. Has evidence of untreated CNS metastases (exception: participants with primary CNS tumors and leptomeningeal disease)
  8. Has GI malabsorption, GI anastomosis, or any other condition that in the opinion of the investigator might affect the absorption of lenvatinib
  9. Has preexisting ≥Grade 3 GI or non-GI fistula
  10. Has any active infection requiring systemic therapy
  11. A clinically significant ECG abnormality, including a marked baseline prolonged QT or QTc interval (eg, a repeated demonstration of a QTc interval >480 msec)
  12. Known to be HIV positive.  Note: HIV testing is required at screening only when mandated by local health authority.
  13. Active viral hepatitis (B or C) as demonstrated by positive serology.  Note: Testing for hepatitis B or hepatitis C is required at screening only when mandated by local health authority.

Prior/Concomitant Therapy | Clinical Study Experience

  1. Is currently participating and receiving study therapy, or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the date of allocation.  Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.

Diagnostic Assessments Other Exclusions

  1. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant’s participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator
  2. Has known hypersensitivity to any component of the investigational product (lenvatinib or ingredients)
  3. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study


  • Dallas, TX - Mary Crowley Cancer Research - Medical City
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Re: MC# 20-18