| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Primary central nervous system tumors |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065143 |
| E.1.2 | Term | Malignant solid tumour |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Dose Escalation Part 1
1. To evaluate the safety and tolerability of avelumab + lenvatinib
2. To determine the recommended avelumab and lenvatinib dose for expansion
Dose Expansion Part 2
1. To assess efficacy by PFS |
|
| E.2.2 | Secondary objectives of the trial |
Dose Escalation Part 1
1. To assess PFS based on Investigator assessments and OS
Dose Expansion Part 2
1. To assess the OS
Dose Escalation Part 1 and Dose Expansion Part 2
1. To further evaluate the safety and tolerability of avelumab + lenvatinib
2. To assess antitumor activity of avelumab + lenvatinib by ORR and DoR
3. To characterize the PK profile of avelumab and lenvatinib when administered in combination.
4. To characterize the immunogenicity of avelumab in combination with lenvatinib |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Are ≥ 2 and < 18 years of age at the time of signing the informed consent.
2. A histologically confirmed diagnosis of primary CNS malignancy as follows:
-Primary CNS tumors
The tumor should be considered high-grade histologically
Prior radiotherapy is allowed
Participants must have progressed after they have been treated based on current treatment guidelines.These treatments are administered until the end of protocol, progressive disease or unacceptable toxicity.
-Specific for participants with diffuse midline glioma with or without the H3 K27M mutation
Prior radiotherapy is allowed
No more than 1 prior systemic therapy is allowed
Note: Participants with diffuse midline glioma with or without the H3 K27M
mutation who have not received prior systemic therapy but have prior radiotherapy only are allowed to enroll.
3. On screening scans, measurable disease by RANO criteria.
4. Participants must have a Lansky performance status ≥ 50 for age ≤ 16 years or Karnofsky performance status ≥ 50 for age > 16 years at Screening.
5. Adequate bone marrow function at Screening
Absolute neutrophil count must be ≥ 1000/μL.
Platelet count must be ≥ 100,000/mm3.
Hemoglobin must be ≥ 8 g/dL.
6. Adequate renal function: Screening serum creatinine must be ≤ 1.5 × upper limit of normal (ULN) or creatinine clearance > 70 mL/minute if serum creatinine > 1.5 × ULN, according to the Cockcroft-Gault formula or by 24-hour urine collection for creatinine clearance or according to local institutional standard method.
7. Adequate hepatic function
Screening total bilirubin must be ≤ 1.5 × ULN for age or direct bilirubin ≤ ULN for age if total bilirubin > 1.5 × ULN for age.
Screening serum aspartate aminotransferase (AST) and ALT must be ≤ 3 × ULN for age.
8. Screening prothrombin time/international normalized ratio (INR) must be ≤ 1.5 × institutional ULN for age.
9. Availability of tissue as a formalin-fixed paraffin-embedded (FFPE) block or a minimum of 10 (preferably 25) unstained tumor slides suitable for PD-L1 expression assessment. Tumor tissue from the most recent biopsy should be submitted, and this should be from a nonirradiated area.
10. A negative serum pregnancy test at Screening for all postmenarchal girls, girls ≥ 10 years of age, or per local or institutional guidelines must be obtained.
11. For participants of childbearing potential: agreement to remain abstinent or use 2 adequate methods of contraception for the duration of study intervention period and at least for 60 days after stopping the study interventions.
12. A fractional shortening ≥ 30% or left ventricular ejection fraction ≥ 50% by echocardiogram or multigated acquisition (MUGA) scan within 28 days of study intervention initiation must be demonstrated.
13. Participants with seizures that are well controlled are eligible and may be on antiepileptic medications, provided the dose of the antiepileptic drug(s) is/are stable.
14. Participant must demonstrate an ability to comply with study protocol.
15. Are male and/or female.
a. Female participants
Are not pregnant or breastfeeding, and at least one of the following conditions applies:
Not a woman of childbearing potential
OR
If a woman of childbearing potential, use a highly effective contraceptive method (i.e., with a failure rate of < 1% per year), preferably with low user dependency, for the following time periods:
Before the first dose of the study intervention(s), if using hormonal
contraception:
Has completed at least one 4-week cycle of an oral contraception pill and
either had or has begun her menses
OR
Has used a depot contraceptive or extended-cycle oral contraceptive for
least 28 days and has a documented negative pregnancy test using a highly
sensitive assay.
Highly effective contraceptive method has to be used for at least 60 days after
the last dose of study intervention.
Additional requirements for pregnancy testing during and after study intervention
The Investigator reviews the medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a female with an early undetected pregnancy.
b. Male participants
-Agree to the following during the study intervention period and for at least 60 days after the last dose of study intervention:
-Refrain from donating sperm PLUS, either Abstain from any activity that allows for exposure to ejaculate
OR Use a male condom:
-When having sexual intercourse with a woman of childbearing potential, who
is not currently pregnant, and advise her to use a highly effective
contraceptive method with a failure rate of < 1% per year, since a condom may break or leak.
16. Participant and/or his/her parent(s)/legal representative(s) is capable of giving signed informed consent, as indicated in Appendix 2 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and this protocol. |
|
| E.4 | Principal exclusion criteria |
1. Participants with low-grade gliomas, for example but not limited to, subependymal giant cell astrocytoma, pilocytic astrocytoma and WHO Grade 1 tumors.
2. Participants demonstrating evidence of worsening of neurologic deficit within 1 week prior to initiation of study interventions.
3. Participants with bulky tumor
4. Participants are not eligible if they experience uncontrolled seizures
5. Participants who have received major surgery within 28 days prior to the first dose of study interventions.
6. A history of intracranial hemorrhage/spinal cord hemorrhage within 28 days prior to the first dose of study interventions.
7. Participants require therapeutic anticoagulation.
8. Participants with a history of bleeding diathesis or recent major bleeding events considered by the Investigator as high risk for investigational drug treatment.
9. Participants with urine protein ≥ 1 g protein/24-hour will be ineligible.
10. Gastrointestinal malabsorption, GI anastomosis, or any other condition that might affect absorption of lenvatinib.
11. Clinically significant cardiovascular or cerebrovascular disease
12. Active hemoptysis (bright red blood of at least 2.5 mL) within 3 weeks prior to the first dose of study interventions.
13. Participants with active hepatitis B or hepatitis C infections.
14. Participants with known human immunodeficiency virus infection.
15. Participants with a serious nonhealing wound, ulcer or bone fracture.
16. The participant has known hypersensitivity to any of the study interventions or any components in their formulations, any history of anaphylaxis, or recent (within 5 months) history of uncontrollable asthma.
17. Prior solid organ transplantation.
18. Severe and/or clinically relevant acute or chronic diseases which, might impair the participant’s tolerance for the study or ability to consistently participate in study procedures.
19. Participants with current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with participation for the full duration of the study.
20. Pregnancy or breast feeding.
21. Any other active malignancy within the past 2 years of Screening.
22. The participant is affected with an autoimmune disease necessitating steroid therapy or other immunomodulatory therapy within the past 2 years of Screening
23. Known active alcohol or drug abuse.
Prior/Concomitant Therapy
24. The participant has received treatment with chemotherapy, differentiation therapy, or other immunotherapy within 3 weeks of study entry.
25. The participant has received prior therapy with anti-PD-1, anti-PD-L1, anti-CTLA4 or CD137 directed therapy.
26. The participant has received prior treatment with lenvatinib or any tyrosine kinase inhibitor.
27. Requirement for daily doses of steroids > 8 mg of methylprednisolone (or equivalent).
28. The participant is experiencing any nonhematologic toxicity from prior treatment that has not resolved to Grade ≤ 1 per (CTCAE) Version 5.0 at Screening.
29. The participant has an active infection necessitating systemic treatment with antibiotics, antifungals, antivirals or steroids within 72 hours of the first dose of study intervention.
30. Prior allogeneic stem cell transplant within the last 5 years.
31. The participant has received any hematopoietic growth factor within 2 weeks of study entry.
32. The participant has received transfusion of packed red blood cells or platelets within 2 weeks before Screening to meet eligibility criteria.
33. The participant has interstitial lung disease OR has a history of drug-induced pneumonitis.
34. The participant has received treatment with live vaccines or live attenuated vaccines within 4 weeks prior to the first dose of avelumab.
35. The participant has received treatment with herbal anticancer therapy within 1 week of study entry.
Prior/Concurrent Clinical Study Experience
36. The participant has received investigational therapy within 5 half-lives or 28 days of study entry.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Dose Escalation Part 1
1. Occurrence and severity of CTCAE Grade ≥ 3 TEAEs according to NCI-CTCAE Version 5.0.
2. Occurrence of DLTs
Dose Expansion Part 2
1. PFS as assessed by Investigators according to RANO criteria |
|
| E.5.2 | Secondary end point(s) |
Dose Escalation Part 1
1. PFS per RANO criteria
Dose Escalation Part 1 and Dose Expansion Part 2
1. Occurrence and severity of any grade TEAEs, treatment-related AEs, AESIs, deaths, and clinically significant changes in laboratory parameters.
2. Confirmed objective response as assessed by Investigators according to RANO criteria
3. DoR according to RANO criteria assessed by Investigator.
4. Overall Survival
5. PK parameters including CEOI, AUC, Ctrough of avelumab; Cmax, tmax, and AUC of lenvatinib of at least a single dose as data permit.
6. Immunogenicity of avelumab as measured by ADA assay |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Evaluation of Avelumab and Lenvatinib in Paediatric Patient |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 4 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| Korea, Republic of |
| United States |
| France |
| Germany |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of the study is defined as minimum follow-up of 12 months after the last administration of study intervention or until the objectives of the study are assessed, whichever comes first. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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