Study of Avelumab in combination with Lenvatinib for children with primary CNS tumors

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Merck Healthcare KGaA

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

24 Nov 2021 → ongoing

Decision date (initial)

2024-07-01

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Merck Healthcare KGaA

External identifiers

EU CT number

2024-512940-51-00

EudraCT number

2020-004397-22

ClinicalTrials.gov

NCT05081180

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Others

Dose Escalation Part 1
To evaluate the safety and tolerability of avelumab + lenvatinib
Dose Escalation Part 1
To determine the recommended avelumab and lenvatinib dose for expansion
Dose Expansion Part 2
To assess efficacy by PFS

Secondary objectives 10

1. Dose Escalation Part 1 To further evaluate the safety and tolerability of avelumab + lenvatinib
2. Dose Escalation Part 1 To assess antitumor activity of avelumab + lenvatinib by ORR and DoR
3. Dose Escalation Part 1 To assess the PFS based on Investigator assessments and OS
4. Dose Escalation Part 1 To characterize the PK profile of avelumab and lenvatinib when administered in combination
5. Dose Escalation Part 1 To characterize the immunogenicity of avelumab in combination with lenvatinib
6. Dose Expansion Part 2 To further evaluate the safety and tolerability of avelumab + lenvatinib
7. Dose Expansion Part 2 To assess antitumor activity of avelumab + lenvatinib by ORR and DoR
8. Dose Expansion Part 2 To assess the OS
9. Dose Expansion Part 2 To characterize the PK profile of avelumab and lenvatinib when administered in combination
10. Dose Expansion Part 2 To characterize the immunogenicity of avelumab in combination with lenvatinib

Conditions and MedDRA coding

Central Nervous System Tumors

Study design 1 period

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-001849-PIP02-15

Plan to share IPD

No

IPD plan description

We are committed to enhancing public health through responsible sharing of clinical trial data. Following approval of a new product or a new indication for an approved product in both the US and European Union, the study sponsor and/or its affiliated companies will share study protocols, anonymized patient data and study level data, and redacted clinical study reports with qualified scientific and medical researchers, upon request, as necessary for conducting legitimate research. Further information on how to request data can be found on our website bit.ly/IPD21

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 15

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: a. Primary CNS tumors i The tumor should be considered high-grade histologically ii Prior radiotherapy is allowed iii For all countries except Germany: Participants must have progressed after at least 1 prior systemic therapy, except for those with diffuse midline glioma with or without the H3 K27M mutation (please refer to 2biii). For Germany only: Participants must have progressed after they have been treated based on current treatment guidelines in accordance to standardized treatment protocols, therapy optimization studies, within a disease register or via early access to upcoming standards. These treatments are administered until the end of protocol, until progressive disease, or unacceptable toxicity. Exception for participants with diffuse midline glioma with or without the H3 K27M mutation (please refer to 2biii). b. Specific for participants with diffuse midline glioma with or without the H3 K27M mutation i Prior radiotherapy is allowed ii No more than 1 prior systemic therapy is allowed iii 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 a. Screening total bilirubin must be ≤ 1.5 × ULN for age or direct bilirubin ≤ ULN for age if total bilirubin > 1.5 × ULN for age. b. 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 Refer to the Protocol for full list of criterias

Exclusion criteria 37

1. Participants with low-grade gliomas, for example but not limited to, subependymal giant cell astrocytoma, pilocytic astrocytoma and WHO Grade 1 tumors.
2. Gastrointestinal malabsorption, GI anastomosis, or any other condition that might affect absorption of lenvatinib.
3. Clinically significant cardiovascular or cerebrovascular disease
4. Active hemoptysis (bright red blood of at least 2.5 mL) within 3 weeks prior to the first dose of study interventions.
5. Participants with active hepatitis B or hepatitis C infections.
6. Participants with known human immunodeficiency virus infection.
7. Participants with a serious nonhealing wound, ulcer or bone fracture.
8. Participants demonstrating evidence of worsening of neurologic deficit within 1 week prior to initiation of study interventions.
9. Participants with bulky tumor
10. Participants are not eligible if they experience uncontrolled seizures
11. Tumor surgeries a. Participants eligible for tumor surgery. b. Participants who have received major surgery (including but not limited to neurosurgical resection, brain biopsy, or radiation to the primary brain tumor) within 28 days prior to the first dose of study interventions.
12. A history of intracranial hemorrhage/spinal cord hemorrhage within 28 days prior to the first dose of study interventions.
13. Participants require therapeutic anticoagulation.
14. Participants with a history of bleeding diathesis or recent major bleeding events considered by the Investigator as high risk for investigational drug treatment.
15. Participants with urine protein ≥ 1 g protein/24-hour will be ineligible.
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, in the opinion of the Investigator, 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, or is not in the best interest of the participant, in the opinion of the treating Investigator.
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.
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-PDL1, 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 druginduced 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.
36. Prior/Concurrent Clinical Study Experience: The participant has received investigational therapy within 5 halflives or 28 days of study entry.
37. Any other reason that, in the opinion of the Investigator, precludes the participant from participating in the study.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Dose Escalation Part 1 Occurrence and severity of CTCAE Grade ≥ 3 TEAEs according to NCICTCAE Version 5.0.
2. Dose Escalation Part 1 Occurrence of DLTs
3. Dose Expansion Part 2 PFS as assessed by Investigators according to RANO criteria

Secondary endpoints 6

1. Dose Escalation Part 1 and Dose Expansion Part 2 Occurrence and severity of any grade TEAEs, treatment-related AEs, AESIs, deaths, and clinically significant changes in laboratory parameters.
2. Dose Escalation Part 1 and Dose Expansion Part 2 Confirmed objective response as assessed by Investigators according to RANO criteria
3. Dose Escalation Part 1 PFS per RANO criteria and Overall Survival
4. Dose Expansion Part 2 Overall Survival
5. Dose Escalation Part 1 and Dose Expansion Part 2 PK parameters including CEOI, AUC, Ctrough of avelumab; Cmax, tmax, and AUC of lenvatinib of at least a single dose as data permit.
6. Dose Escalation Part 1 and Dose Expansion Part 2 Immunogenicity of avelumab as measured by ADA assay

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 7

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Merck Healthcare KGaA

Sponsor organisation

Merck Healthcare KGaA

Address

Frankfurter Strasse 250

City

Darmstadt

Postcode

64293

Country

Germany

Scientific contact point

Organisation

Merck Healthcare KGaA

Contact name

Global Regulatory Affairs

Public contact point

Organisation

Merck Healthcare KGaA

Contact name

Global Regulatory Affairs

Third parties 9

Locations

2 EU/EEA countries · 5 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Temporary halts 2 · Art. 38 CTR

Application history

3 submissions — initial application plus substantial / non-substantial modifications