Trial Title:
M-CHOP in Richter´s Syndrome
NCT ID:
NCT06521996
Condition:
Richter Syndrome
Chronic Lymphocytic Leukemia
Conditions: Official terms:
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Syndrome
Prednisone
Cyclophosphamide
Doxorubicin
Vincristine
Conditions: Keywords:
Chronic lymphocytic leukemia, Richter´s syndrome
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Intervention model description:
Induction Phase:
Cycles 1-2: Step-up Phase: Weekly step-up dosing of mosunetuzumab IV (4-hour infusions)
in 21-day cycles. Doses: 1/2/30 mg on C1D8/C1D15/C2D1, with C2D1 and subsequent doses
fixed at 30 mg. Safety monitored by an Independent Medical Committee (IMC). First five
patients at each dose hospitalized for 48 hours.
Cycles 3-6: Fixed Dose Phase: Mosunetuzumab (30 mg) combined with CHOP (M-CHOP) every 21
days. Disease evaluated by PET/CT after cycles 3 and 6. Patients with PD are withdrawn.
Maintenance Phase:
Cycles 7-17: Mosunetuzumab monotherapy starts 3 weeks (+2 weeks) after EoI. Administered
over eleven 21-day cycles (approx. 10 months) for patients with stable disease (SD),
partial response (PR), or complete response (CR) not eligible for cellular therapy until
disease progression or unacceptable toxicity.
Final Evaluation:
Post-Treatment: Tumor response by PET/CT 8-12 weeks after last dose at Cycle 17 or early
discontinuation to confirm disease progression.
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Biological
Intervention name:
Mosunetuzumab
Description:
Cycle 1: d8, 1 mg; d15, 2 mg
Cycle 2 and beyond: 30 mg
Arm group label:
M-CHOP (Mosunetuzumab combined with CHOP)
Intervention type:
Drug
Intervention name:
CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)
Description:
Cyclophosphamide will be administered at a dose of 750 mg/ m2 IV on Day 1 of Cycle 1-6,
every 21 days.
Doxorubicin will be administered at a dose of 50 mg/m2 IV on Day 1 of Cycle 1-6, during
induction treatment.
Vincristine will be administered at a dose of 1.4 mg/m2 (maximum 2 mg) IV infusion in 50
ml sodium chloride 0.9% over 10 minutes on Day 1 of Cycle 1-6, every 21 days.
Methylprednisolone will be administered at fixed dose of dose 80 mg IV on Day 1 of Cycle
1-6, every 21 days.
Prednisone will be administered at a dose of 60 mg/m2 orally on Days 2-5 of Cycle 1-6,
every 21 days.
Arm group label:
M-CHOP (Mosunetuzumab combined with CHOP)
Summary:
The purpose of the study is to assess the efficacy, safety and tolerability of
mosunetuzumab combined with CHOP in patients with untreated DLBCL-RS syndrome,
identifying biological factors to address the probability of response.
In addition, efficacy and tolerability of maintenance with mosunetuzumab in patients not
receiving an allo-SCT will be ascertained.
Detailed description:
The primary study objective and associated endpoint is to evaluate the efficacy of
mosunetuzumab combined with CHOP (M-CHOP) after the end of induction (EoI) in patients
with RS who have never received therapy.
Primary endpoint will be complete remission (CR) evaluated by an independent review
committee according to modified Lugano classification using PET/CT scan after the EoI
visit. CR is defined as a score of 1, 2 or 3 for lymph nodes and extra-lymphatic sites at
PET without new lesions and no evidence of fluorodeoxyglucose (FDG)-avid disease in bone
marrow. All PET evaluable in patients with at least one dose of mosunetuzumab will be
included in the efficacy population.
The secondary study objectives and associated endpoints are:
- To evaluate the efficacy of mosunetuzumab combined with CHOP (M-CHOP) after the end
of induction (EoI) and maintenance (EoM) in patients with therapy naive RS.
- Overall response rate (ORR), defined as the proportion of participants with a
complete response (CR) or partial response (PR) at the end of induction (EoI) and
maintenance (EoM), as determined by local and independent review committee according
to modified Lugano classification using PET/CT scan and IWCLL criteria (Hallek
2018).
- Complete remission (CR) at the EoM will be defined as a score of 1, 2 or 3 (no
uptake above background) for lymph nodes and extralymphatic sites at PET without new
lesions and no evidence of fluorodeoxyglucose (FDG)-avid disease in bone marrow. In
addition, patients need to have a normal blood count with
normal/immunohistochemistry (IHC)-negative bone marrow morphology as per iwCLL
criteria (Hallek 2018). All PET evaluable patients with at least one dose of
mosunetuzumab will be included in the efficacy population.
- Best overall response: the best response is defined as the achievement of a PET
score of 1-3 associated with a normal blood count with normal/immunohistochemistry
(IHC)-negative bone marrow morphology as per iwCLL criteria, or a PET score of 1-3
associated with incomplete recovery in blood and normal/immunohistochemistry
(IHC)-negative bone marrow morphology evaluated at any time during the treatment
induction or maintenance, whichever occurs first.
- Minimal residual disease (MRD) response rate determined by the proportion of
patients with MRD-negativity (defined as < 1 CLL cell in 10,000 leukocytes),
assessed by flow cytometry in responders (CR/PR) in peripheral blood (PB) and/or
bone marrow (BM) after the EoI and EoM.
- Progression free survival (PFS), defined as the time from the first study treatment
to the first occurrence of disease progression or death from any cause, whichever
occurs first. PFS will be assessed by the investigator, using the Lugano criteria.
- Overall survival (OS), defined as the time from first dose to death from any cause.
- Duration of response (DoR), defined as the time from best overall response (the
first occurrence of a documented objective response) to disease progression by
Lugano criteria or death from any cause, whichever occurs first.
To determine the incidence and severity of adverse events
- Incidence of adverse events (AEs): number and percentage of patients with 1 or more
AE.
- Severity of AEs according to NCI CTCAE v5.0. For events of CSR, severity will be
determined by ASTCT CSR consensus grading criteria. For events of TLS, the presence
of laboratory and/or clinical TLS will be determined according to Howard criteria.
To evaluate the study treatment exposure:
- Treatment duration
- Total dose received
- Number of cycles and dose modifications
- Treatment interruptions and discontinuations
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Patients meeting all the following inclusion criteria will be eligible for
participation in the study:
1. Capable of giving signed informed consent as described in Section 13.2, which
includes compliance with the requirements and restrictions listed in the
Informed Consent Form and this protocol.
2. Aged between 18 and 79 years at the time of signing the Informed Consent Form
3. Ability to comply with the study protocol and procedures and required
hospitalizations, in the investigator's judgement.
4. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤2.
5. Adult patients with previously untreated, histologically proven Richter's
syndrome, diffuse large B cell variants, following WHO 2008 criteria (Swerdlow
SH, 2008).
6. Screening flow cytometry or immunohistochemistry (IHC) evidence of CD20
positive disease as per central review (dim expression of CD20 is acceptable)
7. Adequate BM function independent of growth factor or transfusion at screening
as follows unless cytopenia is clearly due to marrow involvement of CLL:
1. Platelet count ≥75 x 109/L; in cases of thrombocytopenia clearly due to
marrow involvement of CLL (per the discretion of the investigator),
platelet count should be ≥ 30 x 109/L.
2. ANC ≥1 x 109/L unless neutropenia is clearly due to marrow involvement of
CLL (per the discretion of the investigator)
3. Total hemoglobin ≥ 9 g/dL unless anemia is due to marrow involvement of
CLL (per the discretion of the investigator)
8. Measured or estimated creatinine clearance ≥ 45 mL/min by institutional
standard method.
9. Life expectancy > 3 months
10. For women of childbearing potential (WOCBP): agreement to remain abstinent
(refrain from heterosexual intercourse) or use contraceptive methods that
result in a failure rate of < 1% per year, and agreement to refrain from
donating eggs, during the treatment period and for at least 3 months after the
last dose of mosunetuzumab and 3 months after the last dose of tocilizumab (if
applicable).
1. It is recommended to remain abstinent or use contraception for 12 months
after the final dose of cyclophosphamide, doxorubicin, or vincristine.
2. A woman is considered to be of childbearing potential (WOCBP) if she is
postmenarchal, has not reached a postmenopausal state (≥ 12 continuous
months of amenorrhea with no identified cause other than menopause), and
is not permanently infertile due to surgery (i.e., removal of ovaries,
fallopian tubes, and/or uterus) or another cause as determined by the
investigator (e.g., Müllerian agenesis). The definition of childbearing
potential may be adapted for alignment with local guidelines or
regulations.
Examples of contraceptive methods with a failure rate of < 1% per year include bilateral
tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation,
hormone-releasing intrauterine devices, and copper intrauterine devices.
Exclusion Criteria:
1. Pregnant or breastfeeding or intending to become pregnant during the study or within
3 months after the final dose of mosunetuzumab.
a) WOCBP must have a negative serum pregnancy test result within 14 days prior to
initiation of study treatment. If a serum pregnancy test has not been performed
within 14 days prior to receiving first study treatment, a negative urine pregnancy
test result (performed within 7 days prior to study treatment) must be available.
2. Participants who have received any of the following treatments prior to study entry:
a) Treatment with mosunetuzumab or other CD20/CD3-directed bispecific antibodies.
3. Participants who have received any of the following treatments, whether
investigational or approved, given to treat RS, within the respective time periods
prior to initiation of study treatment:
1. Autologous SCT within 100 days prior to first mosunetuzumab administration.
2. Allogeneic stem cell transplant for CLL
3. CAR T-cell therapy for CLL within 100 days before first study treatment
4. Systemic corticosteroid treatment ≤ 20 mg/day prednisone or equivalent to
control symptoms related to disease progression for a maximum of 5 days before
starting C1D1 and inhaled corticosteroids are permitted.
4. Central nervous system (CNS) involvement as documented by spinal fluid cytology or
imaging.
5. Transformation of CLL to prolymphocytic leukemia.
6. History of prior malignancy, except for conditions as listed below if patients have
recovered from the acute side effects incurred as a result of previous therapy:
1. Malignancies treated with curative intent and with no known active disease
present for ≥ 2 years before enrollment.
2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
of disease.
3. Adequately treated cervical carcinoma in situ without evidence of disease.
4. Surgically/adequately treated low grade, early stage, localized prostate cancer
without evidence of disease.
7. Any of the following laboratory abnormalities:
1. Calculated creatinine Clearance < 45 mL/min (by institutional standard
method.).
2. Absolute neutrophil count (ANC) < 1.0 x 109/L, unless secondary to bone marrow
involvement by CLL.
3. Platelet count <75 x 109/L except if thrombocytopenia is clearly due to marrow
involvement of CLL (per the discretion of the investigator) for which exclusion
criteria would be platelet count < 30 x 109/L.
4. Serum aspartate aminotransferase (AST)/serum glutamic-oxaloacetictransaminase
(SGOT) or alanine transaminase (ALT)/serum glutamate pyruvate transaminase
(SGPT) >2.5 x upper limit of normal (ULN).
5. Serum total bilirubin > 1.5 x ULN, except in cases of Gilbert's syndrome.
8. History of severe allergic or anaphylactic reactions to humanized or murine
monoclonal antibody therapy (or recombinant antibody-related fusion proteins)
9. Contraindication to tocilizumab.
10. Presence of any autoimmune disorder including autoimmune hemolytic anemia or
autoimmune thrombocytopenia active at the moment of first dose of therapy.
a) Participants with a history of disease-related immune thrombocytopenic purpura or
autoimmune hemolytic anemia may be eligible.
11. History of autoimmune disease, including, but not limited to, myasthenia gravis,
myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis,
inflammatory bowel disease, vascular thrombosis associated with antiphospholipid
syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome,
multiple sclerosis, vasculitis, or glomerulonephritis. Exceptions include the
following:
1. Participants with a history of autoimmune-related hypothyroidism on a stable
dose of thyroid replacement hormone may be eligible.
2. Participants with controlled Type 1 diabetes mellitus who are on an insulin
regimen are eligible for the study.
3. Participants with a remote history of, or well-controlled autoimmune disease,
with a treatment-free interval from immunosuppressive therapy for 12 months may
be eligible after review and discussion with the Coordinators.
12. History of solid organ transplantation
13. Participants with infections requiring IV treatment with antibiotics or
hospitalization (Grade 3 or 4) within the last 4 weeks prior to enrollment or known
active bacterial, viral (including SARS-CoV-2), fungal, mycobacterial, parasitic, or
other infection (excluding fungal infections of nail beds) at study enrollment.
14. History of confirmed progressive multifocal leukoencephalopathy (PML)
15. Positive serologic HIV test at screening
16. Positive test results for chronic hepatitis B infection (defined as positive
hepatitis B surface antigen [HBsAg] serology). Participants with occult or prior
hepatitis B infection (defined as positive total hepatitis B core antibody and
negative HBsAg) may be included if hepatitis B virus (HBV) DNA is undetectable at
the time of screening. These participants must be willing to undergo monthly DNA
testing and appropriate prophylactic antiviral therapy as indicated.
17. Acute or chronic hepatitis C virus (HCV) infection. Participants who are positive
for HCV antibody must be negative for HCV by polymerase chain reaction (PCR) to be
eligible for study participation.
18. Known or suspected chronic active Epstein Barr Virus infection (CAEBV).
19. Patients with history of macrophage activation syndrome (MAS)/hemophagocytic
lymphohistiocytosis (HLH)
20. Received a live, attenuated vaccine within 4 weeks before first dose of study
treatment, or in whom it is anticipated that such a live attenuated vaccine will be
required during the study period or within 5 months after the final dose of study
treatment.
21. Left ventricular ejection fraction (LVEF) <50% by multiple-gated acquisition (MUGA)
scan or echocardiogram.
22. Evidence of any significant, concomitant disease that could affect compliance with
the protocol or interpretation of results, including, but not limited to:
1. significant cardiovascular disease (e.g., New York Heart Association Class III
or IV cardiac disease, myocardial infarction within the previous 3 months,
unstable arrhythmia, or unstable angina)
2. significant pulmonary disease (such as obstructive pulmonary disease or history
of bronchospasm)
3. clinically significant history of liver disease, including viral or other
hepatitis, or cirrhosis.
4. current or past history of CNS disease, such as stroke, epilepsy, CNS
vasculitis, or neurodegenerative disease.
5. Participants with a history of stroke who have not experienced a stroke or
transient ischemic attack in the past year and have no residual neurologic
deficits as judged by the investigator are allowed.
6. Participants with a history of epilepsy who have had no seizures in the past 2
years with or without anti-epileptic medications can be eligible.
23. Recent major surgery within 4 weeks prior to first study treatment administration,
with the exception of protocol-mandated procedures (e.g., tumor biopsies and bone
marrow biopsies)
24. Participants who are in dependence to the Sponsor or an investigator.
25. Any serious medical condition or abnormality in clinical laboratory tests that, in
the investigator's judgment, precludes an individual's safe participation in and
completion of the study.
Gender:
All
Minimum age:
18 Years
Maximum age:
79 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
H. Clínic i Provincial
Address:
City:
Barcelona
Country:
Spain
Status:
Recruiting
Contact:
Last name:
Pablo Mozas
Facility:
Name:
H. Vall d'Hebrón
Address:
City:
Barcelona
Country:
Spain
Status:
Not yet recruiting
Contact:
Last name:
Pau Abrisqueta
Facility:
Name:
ICO Duran i Reynals
Address:
City:
Barcelona
Country:
Spain
Status:
Recruiting
Contact:
Last name:
Ana Oliveira
Facility:
Name:
C. H. U. de Gran Canaria Dr. Negrín
Address:
City:
Las Palmas De Gran Canaria
Country:
Spain
Status:
Recruiting
Contact:
Last name:
Alexia Suárez Cabrera
Facility:
Name:
H. U. 12 de Octubre
Address:
City:
Madrid
Country:
Spain
Status:
Recruiting
Contact:
Last name:
Javier de la Serna
Facility:
Name:
H. U. La Princesa
Address:
City:
Madrid
Country:
Spain
Status:
Recruiting
Contact:
Last name:
Luis Miguel Juárez
Facility:
Name:
H. Costa del Sol
Address:
City:
Marbella
Country:
Spain
Status:
Recruiting
Contact:
Last name:
María Ángeles Medina
Facility:
Name:
H. G. U. Morales Meseguer
Address:
City:
Murcia
Country:
Spain
Status:
Recruiting
Contact:
Last name:
Dolores García Malo
Facility:
Name:
H. U. Central de Asturias
Address:
City:
Oviedo
Country:
Spain
Status:
Not yet recruiting
Contact:
Last name:
Ángel Ramírez Páyer
Facility:
Name:
H. U. de Salamanca
Address:
City:
Salamanca
Zip:
37007
Country:
Spain
Status:
Recruiting
Contact:
Last name:
Almudena Navarro Bailón
Facility:
Name:
H. U. de Donostia
Address:
City:
San Sebastián
Country:
Spain
Status:
Recruiting
Contact:
Last name:
Izaskun Zeberio Echechipia
Facility:
Name:
H. U. Marqués de Valdecilla
Address:
City:
Santander
Country:
Spain
Status:
Recruiting
Contact:
Last name:
Ana Méndez
Phone:
+34 942 203450
Email:
administracion@gellc.es
Facility:
Name:
C. H. U. de Santiago
Address:
City:
Santiago De Compostela
Country:
Spain
Status:
Recruiting
Contact:
Last name:
Adrián Mosquera
Facility:
Name:
H. U. Virgen del Rocío
Address:
City:
Sevilla
Country:
Spain
Status:
Recruiting
Contact:
Last name:
Fátima de la Cruz
Facility:
Name:
H. C. U. de Valencia
Address:
City:
Valencia
Country:
Spain
Status:
Recruiting
Contact:
Last name:
Mª José Terol
Facility:
Name:
H. Lozano Blesa
Address:
City:
Zaragoza
Country:
Spain
Status:
Not yet recruiting
Contact:
Last name:
Teresa Olave
Start date:
April 26, 2024
Completion date:
October 1, 2029
Lead sponsor:
Agency:
GELLC (Grupo Español de Leucemia Linfocítica Crónica)
Agency class:
Other
Source:
GELLC (Grupo Español de Leucemia Linfocítica Crónica)
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06521996
https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/leukaemia-cll
https://www.ema.europa.eu/en/appendix-4-guideline-evaluation-anticancer-medicinal-products-man-condition-specific-guidance-scientific-guideline
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/hematologic-malignancies-regulatory-considerations-use-minimal-residual-disease-development-drug-and
https://videocast.nih.gov/summary.asp?Live=16420&bhcp=1
http://seer.cancer.gov/statfacts/html/clyl.html
https://www.semanticscholar.org/paper/A-risk-based-approach-to-immunogenicity-concerns-of-Rosenberg-Worobec/1ab05ec79c61a8a6a43c006d955ab88cbf9f9b28
https://www.semanticscholar.org/paper/A-risk-based-approach-to-immunogenicity-concerns-of-Rosenberg-Worobec/6b899e3494342ac60e4f6bb68dd129a9699457be
https://www.semanticscholar.org/paper/A-risk-based-approach-to-immunogenicity-concerns-of-Rosenberg-Worobec/1ab05ec79c61a8a6a43c006d955ab88cbf9f9b28
https://www.jstatsoft.org/article/view/v094i13
