Transplant BRaVE NHL: Phase I-II study combining Brentuximab Vedotin with second line salvage chemotherapy (R-DHAP) in CD30 positive diffuse large B-cell lymphoma patients refractory to first line chemotherapy or in first relapse who are eligible for high dose treatment followed by autologous stem cell transplantation. Transplant BRaVE NHL

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Hemato-Oncologie voor Volwassenen Nederland (Hovon) Stichting

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

5 Mar 2018 → ongoing

Decision date (initial)

2024-11-25

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Takeda

External identifiers

EU CT number

2023-510556-22-00

EudraCT number

2016-001211-21

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Therapy

Phase 1 part:
- To identify the feasibility and RDL (recommended dose level) of brentuximab vedotin in combination with R-DHAP
Phase 2 part:
- To evaluate the efficacy of the combination of brentuximab -vedotin and R-DHAP as salvage treatment in relapse/refractory DLBCL patients in terms of metabolic CR rate after the third cycle
- To establish the rate of CTCAE grade 3/4 non-hematological toxicity, including neurotoxicity after each cycle of brentuximab vedotin-R-DHAP

Secondary objectives 10

1. Phase 1 part: To assess the toxicity of brentuximab vedotin in combination with R-DHAP
2. Phase 1 part: To assess the success rate of autologous peripheral blood stem cell harvest after brentuximab vedotin-R-DHAP
3. Phase 2 part: To asses the overall response rate (ORR) after 3 cycles and after ASCT
4. Phase 2 part: To assess the toxicity profile of brentuximab vedotin in combination with R-DHAP
5. Phase 2 part: To assess hematological recovery after each cycle of brentuximab vedotin-R-DHAP
6. Phase 2 part: To assess the success rate of harvesting an autologous peripheral blood stem cell graft
7. Phase 2 part: To assess the fraction of patients (CR/PR) eligible for ASCT who actually undergo ASCT
8. Phase 2 part: To assess peripheral blood neutrophil and platelet recovery after ASCT
9. Phase 2 part: To evaluate the progression free survival (PFS), event free survival (EFS), and overall survival (OS)
10. Phase 2 part: To identify predictive factors for response, PFS, EFS and OS (exploratory analysis)

Conditions and MedDRA coding

non-Hodgkin lymphoma (NHL)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 17

1. CD30 positive DLBCL, i.e. more than 1% of DLBCL cells CD30 positive according to the WHO classification 2008: CD30 positive DLBCL, including EBV positive DLBCL. CD30 positive primary mediastinal B-cell lymphoma
2. Primary refractory to or in first relapse after first line therapy with R-CHOP or R-CHOP-like therapy
3. Age ≥ 18 years (upper age limit for ASCT at the discretion of the participating center)
4. Measurable disease: on CT scan at least 1 lesion/node with a long axis of > 1.5 cm and at least one positive lesion on 18F-FDG PET scan
5. WHO performance status 0-2
6. Adequate hepatic function
7. Adequate renal function
8. Adequate bone marrow function
9. Hemoglobin must be ≥ 8 g/dL (5.0 mmol/L), transfusion is allowed
10. Eligible for high-dose chemotherapy and ASCT
11. Resolution of relevant toxicities from first-line therapy
12. Life expectancy of > 3 months with treatment
13. Negative pregnancy test at study entry, if applicable
14. Female patient is either post-menopausal for at least 1 year before screening visit or surgically sterile or if of childbearing potential, agrees to practice 2 effective methods of contraception, at the same time, or agrees to completely abstain from heterosexual intercourse, from the time of signing the informed consent through 12 months after the last dose of study drug
15. Male patients, even if surgically sterilized, (i.e. status post vasectomy) agree to practice effective barrier contraception, or agrees to completely abstain from heterosexual intercourse, during the entire study period and through 12 months after the last dose of study drug
16. Written informed consent
17. Patient is capable of giving informed consent

Exclusion criteria 21

1. Peripheral sensory or motor neuropathy grade ≥ 2
2. Known cerebral or meningeal disease (NHL or any other etiology), including signs and symptoms of progressive multifocal leukoencephalopathy (PML)
3. Symptomatic neurological disease compromising normal activities of daily living or requiring medications
4. Transformed lymphoma
5. DLBCL after organ transplantation
6. Immunodeficiency-associated B-cell lymphoproliferative disease
7. Use of other investigational agents within at least 5 half-lives of the most recent agent used prior to study entry
8. Treatment with myelosuppressive chemotherapy or biological therapy ≤ 4 weeks before study entry
9. Female patients who are breast feeding
10. History of another malignancy less than 3 years before study inclusion, or previously diagnosed with another malignancy and have evidence of residual disease, with the exception of non-melanoma skin cancer, completely resected melanoma TNMpT1 and carcinoma in situ of the uterine cervix
11. Known hypersensitivity to recombinant proteins, murine proteins, or to any excipient contained in the drug formulation of brentuximab vedotin
12. Active hepatitis B or C infection
13. HIV positivity
14. Radiation therapy within 8 weeks prior to start of protocol treatment. Emergency radiation therapy is allowed, as long as measurable disease (at non-irradiated sites) persists
15. Patients with a serious psychiatric disorder that could, in the investigator's opinion, potentially interfere with the completion of treatment according to protocol
16. Major organ dysfunction, unless NHL-related
17. Patients who have any severe and/or uncontrolled medical condition or other conditions that could affect their participation in the study
18. Thyroid abnormalities when thyroid function cannot be maintained in the normal range by medication
19. Current participation in another clinical trial interfering with this trial
20. Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule
21. Claustrophobia to the extent that PET-CT is impossible

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Phase 1 part: The rate of patients with serious toxicity during cycle 1-2 of the combination BV-R-DHAP. Phase 2 part: 1) Primary efficacy endpoint: Metaftabolic CR rate (PET-diagnostic CT) er the third cycle of BV-R-DHAP salvage therapy. 2) Primary feasibility/toxicity endpoints: Rate of grade 3/4 non-hematological toxicity, including neurotoxicity after each cycle of BV-R-DHAP

Secondary endpoints 16

1. Phase 1 part: (Serious) Adverse Events during combination treatment
2. Phase 1 part: Time to hematological recovery after each cycle of BV-R-DHAP
3. Phase 1 part: Time to recovery from non-hematological toxicity after each cycle of BV-R-DHAP
4. Phase 1 part: Administration of treatment: dose reductions, interval between cycles, discontinuation rate
5. Phase 1 part: Rate of successful PBSC collection (≥ 2x106 CD34+ cells/kg) after the third cycle of BV-R-DHAP
6. Phase 2 part: Overall response rate (PR + CR) after the third cycle of BV-R-DHAP salvage therapy (based on the results of the FDG-PET/CT scan)
7. Phase 2 part: Overall response rate (PR + CR) after ASCT (based on the results of the FDG-PET/CT scan)
8. Phase 2 part: Metabolic CR rate (PET-CT) after ASCT
9. Phase 2 part: Fraction of patients (CR/PR) eligible for ASCT who actually undergo ASCT
10. Phase 2 part: Progression free survival (PFS), Event free survival (EFS), Overall survival (OS)
11. Phase 2 part: (Serious) Adverse Events during the combination treatment
12. Phase 2 part: Time to hematological recovery after each cycle of BV + R-DHAP
13. Phase 2 part: Administration of treatment: dose reductions, interval between courses, discontinuation rate
14. Phase 2 part: Rate of successful PBSC collection (≥ 2 x106 CD34+ cells/kg) after the second or third cycle of BV-R-DHAP
15. Phase 2 part: Time to hematological recovery after ASCT
16. Phase 2 part: (Serious) Adverse Events after ASCT

Investigational products

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

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Hemato-Oncologie voor Volwassenen Nederland (Hovon) Stichting

Sponsor organisation

Hemato-Oncologie voor Volwassenen Nederland (Hovon) Stichting

Address

Dr. Molewaterplein 40

City

Rotterdam

Postcode

3015 GD

Country

Netherlands

Scientific contact point

Organisation

Hemato-Oncologie voor Volwassenen Nederland (Hovon) Stichting

Contact name

P.J. Lugtenburg

Public contact point

Organisation

Hemato-Oncologie voor Volwassenen Nederland (Hovon) Stichting

Contact name

HOVON

Third parties 2

Locations

3 EU/EEA countries · 16 investigational sites

By country

Investigational sites

Country notifications

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

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 9 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

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