This study has been transitioned to CTIS with ID 2023-504994-19-00 check the CTIS register for the current data. This Phase II, open-label, multicenter study, will evaluate the safety, efficacy, and pharmacokinetics of glofitamab in combination with…
ID
Source
Brief title
Condition
- Lymphomas non-Hodgkin's B-cell
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary objective:
To evaluate the efficacy of glofitamab in combination with R-CHOP in ctDNA
high-risk patients with previously untreated DLBCL
Corresponding endpoint:
EOT CR rate, as determined by the investigator according to the 2014 Lugano
Response Criteria.
Secondary outcome
Secondary objectives:
- To evaluate the efficacy of glofitamab in combination with R-CHOP in ctDNA
high-risk patients with previously untreated DLBCL
- To evaluate the safety of glofitamab in combination with R-CHOP in ctDNA
high-risk participants with DLBCL
- To characterize the serum PK profile of glofitamab in combination with R-CHOP
- To evaluate potential effects of ADAs
Corresponding endpoints:
- ORR at the EOT, as determined by the investigator according to the 2014
Lugano Response Criteria
- PFS, defined as the time from the first study treatment to the first
occurrence of disease progression or relapse, as determined by the investigator
according to the 2014 Lugano Response Criteria
- OS, defined as the time from the first study treatment to death from any cause
- Incidence and severity of adverse events, with severity determined according
to NCI CTCAE v5.0
- Tolerability, as assessed by dose modifications, dose intensity, and study
- Serum concentrations of glofitamab at specified timepoints
- Serum trough concentrations of glofitamab at specified timepoints
- Glofitamab PK parameters (e.g., Cmax, AUC), as appropriate
- Relationship between ADA status and efficacy, safety, or PK endpoints
Background summary
ctDNA high-risk patients are those who fail to achieve at least a 2 log-fold
reduction in ctDNA levels between Day 1 of Cycle 1 (pretreatment) and Day 1 of
Cycle 2. ctDNA is a novel biomarker that offers the potential for an early,
sensitive approach to identifying patients with DLBCL at a higher risk of
front-line treatment failure.
In the front-line setting, a subset of patients with DLBCL have poor outcomes
following treatment with R-CHOP immunochemotherapy. Despite this, R-CHOP
remains the standard-of-care treatment for DLBCL. Efforts to define baseline
prognostic scores and develop biomarkers to improve on the International
Prognostic Index (IPI) and to guide treatment decisions have so far proved
unsuccessful.
In contrast to current baseline prognostic factors, ctDNA has the distinct
advantage of permitting dynamic assessments early during a patient*s treatment
journey and in so doing, identify newly diagnosed individuals with suboptimal
responses to immunochemotherapy who will likely progress in the absence of a
change in treatment strategy and therefore may benefit from therapy
intensification with glofitamab.
Study objective
This study has been transitioned to CTIS with ID 2023-504994-19-00 check the CTIS register for the current data.
This Phase II, open-label, multicenter study, will evaluate the safety,
efficacy, and pharmacokinetics of glofitamab in combination with R-CHOP in
individuals with ctDNA high-risk DLBCL in the first-line setting. Specific
objectives and corresponding endpoints for the study are outlined in Table 3 of
the protocol.
Study design
This is a Phase II, multicenter study evaluating the safety and efficacy of
glofitamab in combination with R-CHOP immunochemotherapy in high-risk
individuals with untreated DLBCL, as assessed by ctDNA.
ctDNA high-risk patients will enroll in the study prior to Cycle 3 of R-CHOP
and commence step-up doses (2.5 mg, 10 mg, and 30 mg) of glofitamab, starting
on Day 8 of Cycle 3). For the purposes of this study, individuals who achieve
at least a 2-log fold reduction in ctDNA.
For enrollment at Cycle 3, eligible patients will be treated with
standard-of-care doses of R-CHOP from Cycle 1. During Cycles 3-6, participants
will be treated with R-CHOP in combination with glofitamab and will receive
glofitamab monotherapy as consolidation during Cycles 7-10.
Participants will be assessed for radiologic tumor response by PET/CT and CT
scans at the end of Cycle 2 (ctDNA screening), following the completion of
treatment, and during the study follow-up period.
Intervention
Glofitamab will be administered on a step-up dosing schedule, starting on Day 8
of Cycle 3 (2.5 mg), Day 15 of Cycle 3 (10 mg), followed by 30 mg on Day 8 of
Cycles 4-6 and Day 1 of Cycles 7-10, with each cycle being 21 days in length
(i.e., every 3 weeks).
Tocilizumab will be administered as a rescue IMP when necessary to participants
who experience a CRS event.
Rituximab (375 mg/m2) will be administered intravenously to participants every
21 days along with CHOP. A locally approved standard-of-care biosimilar
rituximab is permitted.
CHOP Chemotherapy:
CHOP chemotherapy consists of IV cyclophosphamide, IV doxorubicin, vincristine
administered by IV push, and oral prednisone or prednisolone. Standard CHOP
will be administered for six 21-day cycles (including Cycles 1 and 2 during
ctDNA screening) as follows:
• Cyclophosphamide: 750 mg/m2 administered intravenously on Day 1
• Doxorubicin: 50 mg/m2 administered intravenously or according to
institutional guidelines on Day 1
• Vincristine: 1.4 mg/m2 administered by IV push on Day 1 at a recommended cap
of 2 mg
• Prednisone/prednisolone: 100 mg/day orally on Days 1-5 (prednisone on Day 1
may be administered intravenously, with the remaining doses on Days 2-5 to be
administered orally)
Study burden and risks
The general burden for the patient includes taking blood samples, taking tumor
samples (possibly), undergoing scans and administering research products
(intravenously), which can lead to various side effects.
See the Subject Information and Investigator's Brochure for more information on
the risks of the IMPs, non-IMPs, and investigation procedures.
Beneluxlaan 2A
Woerden 3446 GR
NL
Beneluxlaan 2A
Woerden 3446 GR
NL
Listed location countries
Age
Inclusion criteria
• Age 18 years or older at the time of signing Informed Consent Form
• Previously untreated patients with CD20-positive DLBCL, including one of the
following diagnoses made according to the 2016 World Health Organization (WHO)
classification of lymphoid neoplasms
o DLBCL, not otherwise specified, including GCB and ABC/non-GCB types as well
as double-expressor lymphoma (coexpression of MYC and BCL2)
o High-grade B-cell lymphoma (HGBCL) with MYC and BCL2 and/or BCL6
translocations
o Patients with de novo transformed follicular lymphoma
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2
• International Prognostic Index (IPI): 1-5
• Life expectancy of at least 6 months
• Adequate biomarker blood samples prior to initiation of R-CHOP on Day 1 of
Cycle 1 and on Day 1 of Cycle 2 submitted for screening for determination of
ctDNA status
• At least one bi-dimensionally fluorodeoxyglucose (FDG)-avid measurable
lymphoma lesion on positron emission tomography/computed tomography (PET/CT)
scan
• Left ventricular ejection fraction (LVEF) of at least 50%, as determined on
cardiac multiple-gated acquisition (MUGA) scan or cardiac echocardiogram (ECHO)
• Negative HIV test at screening, with the following exception: Patients with a
positive HIV test at screening are eligible provided that, prior to enrollment,
they are stable on anti-retroviral therapy for at least 4 weeks, have a CD4
count ³ 200/µL, have an undetectable viral load, and have not had a history of
an AIDS-defining opportunistic infection within the past 12 months.
• Adequate hematopoietic function
• Contraception use
Additional Inclusion Criterion for ctDNA High-Risk Participants
• Plasma sample evaluated to be ctDNA high risk using the experimental AOA*NHL
Test,, defined as <2-log fold reduction in ctDNA levels between Day 1 of Cycle
1 and Day 1 of Cycle 2 by central laboratory assessment
Exclusion criteria
• Current diagnosis of B-cell lymphoma, unclassifiable, with features
intermediate between DLBCL and classic Hodgkin lymphoma (gray-zone lymphoma),
primary mediastinal (thymic) large B-cell lymphoma, T-cell/histiocyte-rich
large B*cell lymphoma, Burkitt lymphoma, central nervous system (CNS) lymphoma
(primary or secondary involvement), primary effusion DLBCL, and primary
cutaneous DLBCL
• Contraindication to any of the individual components of R-CHOP, including
prior receipt of anthracyclines, history of severe allergic or anaphylactic
reactions to murine monoclonal antibodies, or known sensitivity or allergy to
murine products
• Prior treatment for indolent lymphoma
• Prior solid organ or allogeneic stem cell transplant
• Prior therapy for DLBCL and high-grade B-cell lymphoma (HGBCL) with the
exception of palliative, short-term treatment with corticosteroids
• Pregnant or breastfeeding, or intending to become pregnant during the study
or within 12 months after the final dose of R-CHOP, 3 months after the final
dose of tocilizumab (if applicable), or 2 months after the final dose of
glofitamab
• An exclusion criterion of a positive SARS-CoV-2 test within 7 days prior to
enrollment (including rapid antigen test) has been added
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2023-504994-19-00 |
| EudraCT | EUCTR2021-001647-28-NL |
| ClinicalTrials.gov | NCT04980222 |
| CCMO | NL78443.056.21 |