phase I/II b study of atezolizumab and BEGEV as first salvage treatment in patients with relapsed or refractory Hodgkin’s lymphoma candidate to autologous stem–cell transplantation

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fondazione Italiana Linfomi Ets

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

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

Trial duration

27 Feb 2023 → ongoing

Decision date (initial)

2024-11-12

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Roche S.p.A.

External identifiers

EU CT number

2024-511631-10-00

EudraCT number

2020-002927-13

ClinicalTrials.gov

NCT05300282

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Therapy

Phase I: to determine the maximum tolerated dose (MTD) of the atezolizumab in combination with BEGEV, established in the first cycle of therapy, in order to determine the recommended phase II dose (RP2D).

Phase IIb: to assess the CRR before ASCT according to the Lugano classification response criteria (2014) and the LYmphoma Response to Immunomodulatory Therapy Criteria (LYRIC 2016) by an independent radiologic review committee (IRRC) assessment.

Secondary objectives 8

1. Phase IIb: to assess the overall response rate (ORR), partial response (PR), stable disease (SD) and progression disease (PD) rates.
2. Phase IIb: to assess the rate of PR converted to CR at the end of consolidation treatment with atezolizumab in the experimental arm.
3. Phase IIb: to assess the peripheral blood stem-cell mobilization in patients receiving atezolizumab combined to BEGEV schedule.
4. Phase IIb: to assess engraftment in patients who received ASCT after salvage treatment with atezolizumab combined to BEGEV.
5. Phase IIb: to assess the duration of response (DoR).
6. Phase IIb: to assess PFS and overall survival (OS) for all patients and for patients achieving CR; both parameters will be measured also in long-tem follow up in order to better assess patients’ prognosis.
7. Phase IIb: to assess the safety and the tolerability of a first salvage treatment based on the combination of intravenous (IV) atezolizumab and BEGEV regimen in patients affected by relapsed or refractory cHL.
8. Phase IIb: To evaluate the correlation of quantitative baseline PET parameters with other clinical parameters, response to treatment and outcome.

Conditions and MedDRA coding

Hodgkin’s lymphoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. 18-60 years old (upper limit valid only for phase I).
2. Histologically confirmed cHL: 1) at first disease relapse or refractory to a first-line treatment including: - ABVD/ABVD like regimen - BEACOPP/BEACOPP like regimen - BV-AVD regimen - ABVD/ABVD like (2 cycles) intensified with BEACOPP/BEACOPP like regimen due to persistence of disease at interim positron emission tomography (PET). 2) with documented persistent disease at interim PET (DS4-5) performed after 2 cycles of ABVD/ABVD like regimen.
3. Only one prior systemic therapy for Hodgkin’s lymphoma (HL).
4. Eligibility for ASCT.
5. Performance status (PS) ≤ 2 on the Eastern Cooperative Oncology Group (ECOG) scale.
6. Adequate haematological function, unless due to bone marrow involvement by lymphoma, at the moment of signing informed consent, defined as follows: • neutrophils >= 1.500/mmc and • platelets >=75.000/mmc and • haemoglobin >= 8,0 g/dL with transfusion independence
7. Capacity and willingness to adhere to study visit schedule and specific protocol procedures.
8. Compliance with effective contraception without interruption, according to physician’s judgement, from 28 days before treatment start up to at least 6 months after treatment discontinuation, agreeing not to donate semen/eggs during treatment and for at least 6 months after last treatment dose.

Exclusion criteria 21

1. More than one prior systemic therapy for HL.
2. Presence of autoimmune disease (based on medical history): systemic lupus erythematosus, autoimmune thyroid disease (Hashimoto’s thyroiditis, Basedow’s disease), Sjögren’s syndrome, glomerulonephritis, multiple sclerosis, rheumatoid arthritis, vasculitis, idiopathic pulmonary fibrosis (includine bronchiolitis obliterans organizing pneumonia) and inflammatory bowel disease (Crohn’s disease, ulcerative colitis).
3. Previous skin toxicity (i.e. Steven-Johnson Sdr, severe skin reactions.
4. Prior allogeneic stem cell transplantation or prior solid organ transplant.
5. History of active tubercolosis.
6. History of leptomeningeal disease.
7. Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment.
8. Central nervous system (CNS) involvement by lymphoma.
9. Major surgery (excluding any lymph node biopsy) within 28 days prior to signing informed consent.
10. Seropositivity for HBV or evidence of active infection. The following categories may be considered for the study: • HBsAg positive with undetectable HBV DNA (inactive carriers). • HBsAg negative HBsAb positive and HBcAb negative (vaccinated patients) • HBsAg negative but HBcAb positive from previous infection, providing that they are given antiviral prophylaxis.
11. Seropositivity for HCV. Patients with presence of HCV antibody are eligible only if PCR result are negative for HCV RNA
12. Seropositivity for HIV.
13. Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail bed) or any major episode of infection requiring treatment with IV antibiotics or hospitalization (relating to the completion of the course of antibiotics except if for tumor fever) within 2 weeks of the start of Cycle 1.
14. Life expectancy lower than 6 months.
15. Prior history of malignancies, other than HL, unless the patient has been free for at least 5 years (exceptions: localized non-melanoma skin cancer ad carcinoma in situ of the cervix).
16. Any of the following laboratory abnormalities: liver enzymes (AST/SGOT and/or ALT/SGPT) > 3 fold the upper limit of normal (except of liver involvement by lymphoma); total bilirubin > 1.5 mg/dL (except for patients with known Gilbert’s disease or biliary tree compression by lymphoma masses); creatinine clearance < 30 mL/min.
17. Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina.
18. History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
19. Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab formulation
20. Pregnancy or breastfeeding, or unwillingness to comply with adequate contraception (one negative pregnancy test within 14 days prior to initiation of study treatment required).
21. Any serious medical condition, laboratory abnormality or psychiatric illness that would prevent the patient from signing the informed consent or which may place the patient at unacceptable risk if participating in the study.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Phase I: Phase I: A DLT defined as any of these events occurring during C1 (initial 21 days): - G4 neutropenia leading to delay of next cycle of >14 days; - G4 thrombocytopenia or anemia leading to delay in the of the next cycle of >14 days; - G3 or 4 neutropenia with a fever>38.5 °C and/or infection requiring antibiotic or anti-fungal treatment for >14 days; - G≥3 non-hematologic toxicity persisting for >14 days and not related to study disease; -G≥3 infusion-related toxicities; G≥3 AESIs.
2. Phase IIb: CRR will be defined as the proportion of patients in CR after the first 4 cycles of induction treatment, according to Lugano classification response Criteria and LYRIC 2016 criteria (Appendix D). Patients without response assessment (due to whatever reason) will be considered as non-responders.

Secondary endpoints 8

1. Pahse IIb: ORR, PR, SD, PD rate will be defined according to the Lugano 2014 criteria and LYRIC 2016 criteria.
2. Phase IIb: number of PR converted in CR.
3. Phase IIb: Adequate stem cells mobilization will be defined by the target cell harvesting of 3 x 106 CD34+ cells/kg.
4. Pahse IIb: Engraftment in patients receiving ASCT will be defined as the first of three consecutive days of achieving a sustained peripheral blood neutrophil count of >500 × 106/L (Wolff et al. 2002). Platelet engraftment is usually defined as independence from platelet transfusion for at least 7 days with a platelet count of more than >20 × 109/L (Teltschik et al. 2016).
5. Phase IIb: DoR will be defined as the time from date of documented tumor response (CR) until lymphoma relapse or progression.
6. Pahse IIb: PFS will be defined as the time from beginning of therapy until lymphoma relapse or progression or death as a result of any cause; responding patients and patients who are lost to follow up will be censored at their last assessment date. OS will be defined as the time from beginning of therapy until death as a result of any cause; alive patients and those who are lost to follow up will be censored at their last assessment date.
7. Phase IIb: measurement of: patients’ withdrawal rate, incidence, type and grade of any adverse event (AE) and serious adverse event (SAE), hospitalization rate (except it for study therapy administration), throughout the study.
8. Phase IIb: SUVmax, tMTV (total Metabolic Tumor Volume), TLG (Total Lesion Glycolysis), Dmax and Radiomics features extrapolated by PET scans

Investigational products

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

Test 4

Comparator 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fondazione Italiana Linfomi Ets

Sponsor organisation

Fondazione Italiana Linfomi Ets

Address

Piazza Filippo Turati 5

City

Alexandria

Postcode

15121

Country

Italy

Scientific contact point

Organisation

Fondazione Italiana Linfomi Ets

Contact name

Armando Santoro, MD

Public contact point

Organisation

Fondazione Italiana Linfomi Ets

Contact name

Armando Santoro, MD

Locations

1 EU/EEA country · 32 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 20 files

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

Application history

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