ObinutuzuMab AtezOlizumab and VenetocLax in RichTer transfOrmation

NCT04082897 | Active Not Recruiting Phase 2 DMC

• 1 other identifier: MOLTO
• Study Type: interventional
• Target: 28
• Locations: 2 countries
• Sites: 17

Brief Summary

This study is a multicenter, open-label, uncontrolled, phase II trial aimed to establish the safety and tolerability of venetoclax, atezolizumab and obinutuzumab combination in Richter Transformation of CLL.

Conditions

CLL Transformation

Keywords

Richter Transformation; Safety; Efficacy; Obinutuzumab; Venetoclax; Atezolizumab

Outcome Measures

Primary Outcomes (1)

• Efficacy of the combination venetoclax, obinutuzumab and atezolizumab in terms of Overall Response Rate (ORR)

  The treatment will be considered effective if the combination enables the achievement of a minimum of 67 % ORR at the end of the sixth cycle. Patients will be evaluated according to Lugano Criteria for aggressive lymphomas (Cheson et al. JCO, 2014). Residual underlying CLL may persist in node and/or marrow and still qualify as CR, denoting complete response of Richter Transformation (RT) to treatment (Hallek M et al. IwCLL Criteria Blood 2008).

  First 6 cycles of therapy (each cycle is 21 days)

Secondary Outcomes (5)

• Safety (Incidence of Treatment-Emergent Adverse Events as assessed by NCI-CTCAE v4.0) of the combination venetoclax, obinutuzumab and atezolizumab

  During the entire study duration (estimated to be 7 years)

• Efficacy assessed by CRR of the combination venetoclax, obinutuzumab and atezolizumab

  During the entire study duration (estimated to be 7 years)

• Efficacy assessed by DoR of the combination venetoclax, obinutuzumab and atezolizumab

  During the entire study duration (estimated to be 7 years)

• Efficacy assessed by PFS of the combination venetoclax, obinutuzumab and atezolizumab

  During the entire study duration (estimated to be 7 years)

• Efficacy assessed by OS of the combination venetoclax, obinutuzumab and atezolizumab

  During the entire study duration (estimated to be 7 years)

Study Arms (1)

Combination of Obinutuzumab, Atezolizumab and Venetoclax

EXPERIMENTAL

Obinutuzumab will be administered iv from cycle 1 to cycle 8 : * cycle1: 100 mg iv (day 1) and 900 mg iv (day 2) 1000mg iv (day 8 and day 15) * Cycle 2-8: 1000 mg iv on day 1 Atezolizumab will be administered iv at 1.200 mg fixed dose from C1 to C18: * Cycles 1: day 2 * Cycle 2-18: day 1 Venetoclax will start from day 15 of cycle 1 on a weekly ramp-up basis: week 1: 20 mg (from day 15 cycle 1) week 2: 50 mg (from day 1 to day 7 cycle 2) week 3: 100 mg (from day 8 to day 14 cycle 2) week 4 200 mg (from day 15 to day 21 cycle 2) week 5: 400 mg (from day 1 cycle 3) venetoclax will be thereafter continued until day 21 of cycle 35

Drug: Obinutuzumab 25 MG/ML [Gazyva]; Drug: Atezolizumab 60 MG/ML [Tecentriq]; Drug: Venetoclax Oral Tablet

Interventions

Obinutuzumab 25 MG/ML [Gazyva] DRUG

Obinutuzumab will be administered from C1 to C8

Combination of Obinutuzumab, Atezolizumab and Venetoclax

Atezolizumab 60 MG/ML [Tecentriq] DRUG

Atezolizumab will be administered iv from C1 to C18

Combination of Obinutuzumab, Atezolizumab and Venetoclax

Venetoclax Oral Tablet DRUG

Venetoclax will be administered from day 15 cycle 1) until day 21 of cycle 35

Combination of Obinutuzumab, Atezolizumab and Venetoclax

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Ability to understand and the willingness to sign a written informed consent document
• Signed Informed Consent
• Confirmed diagnosis of chronic lymphocytic leukemia or small lymphocytic lymphoma as IW-CLL 2008 criteria (Hallek et al, 2008) with biopsy proven transformation to diffuse large B cell lymphoma (DLBCL), consistent with Richter's Syndrome
• Age greater than or equal to 18 years
• ECOG performance status \<= 2
• Patients must meet the following hematologic criteria at screening, unless they have significant bone marrow involvement of their malignancy confirmed on biopsy:
• Absolute neutrophil count \>=1000 cells/mm3 (1.0 x 10\^9/L).
• Platelet count \>= 50,000 cells/mm3 (50 x 10\^9/L) within 7 days of screening
• Total hemoglobin \> 9 g/dL (without transfusion support, unless anemia is due to marrow involvement of CLL)
• Subject must have adequate coagulation, renal, and hepatic function, per laboratory reference range at screening as follows:
• Activated partial thromboplastin time (aPTT) and International normalized ratio (INR) \> 1.5 x ULN for patients not receiving therapeutic anticoagulation;
• Creatinine \<= 1.5 x ULN or creatinine clearance \>= 50 mL/min based on Cockcroft-Gault formula;
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \<= 2.5 × ULN;
• Bilirubin \<= 1.5 × ULN;
• Subjects with Gilbert's Syndrome or resolving autoimmunohemolytic anemia may have a bilirubin up to 3.0 × ULN and are still eligible

You may not qualify if:

• Prior treatment for Richter transformation.
• Prior treatment with obinutuzumab anti PD-1 or PDL-1 antibodies.
• Prior treatment with venetoclax.
• Hypersensitivity to obinutuzumab, venetoclax or atezolizumab or their formulation excipients.
• Patients with the Hodgkin variant transformation of CLL.
• Prolymphocytic transformation.
• Patients with a previous history of indolent B cell malignancies other than CLL.
• History of other malignancy other than CLL and Richter syndrome that could affect compliance with the protocol or interpretation of results with the exception of:
• Patients with curatively treated basal or squamous cell carcinoma or stage 1 melanoma of the skin or in situ carcinoma of the cervix
• Patients with a malignancy that has been treated with surgery alone with curative intent. Individuals in documented remission without treatment for \> 2 years prior to enrollment may be included at the discretion of the Sponsor-Investigator.
• Low-risk prostate cancer on active surveillance.
• Evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results or that could increase risk to the patient, including renal disease that would preclude chemotherapy administration or pulmonary disease (including obstructive pulmonary disease and history of bronchospasm).
• Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment, or any major episode of infection requiring treatment with IV antibiotics or hospitalization (relating to the completion of the course of antibiotics) within 4 weeks prior to Cycle1, Day1.
• Clinically significant history of liver disease, including autoimmune hepatitis, current alcohol abuse, or cirrhosis.
• Presence of positive PCR for hepatitis B, hepatitis C or positive hepatitis B surface antigen.

Sponsors & Collaborators

• Niguarda Hospital: lead

Study Sites (17)

Az. Ss.Antonio E Biagio E C.Arrigo - Osp.Civile Ss.Antonio E Biagio

Alessandria, Italy

Location

Asst Papa Giovanni Xxiii

Bergamo, Italy

Location

Azienda Ospedaliero-Universitaria Di Bologna

Bologna, Italy

Location

Asst Degli Spedali Civili Di Brescia

Brescia, Italy

Location

Asst Grande Ospedale Metropolitano Niguarda

Milan, Italy

Location

Fond.Irccs "Istit.Naz.Le Tumori"

Milan, Italy

Location

Fondaz.Irccs Ca' Granda - Ospedale Maggiore Policlinico

Milan, Italy

Location

Irccs S. Raffaele

Milan, Italy

Location

Istituto Europeo Di Oncologia

Milan, Italy

Location

Azienda Osped. Novara E Galliate - Osp. Maggiore Della Carita'

Novara, Italy

Location

Policlinico S. Matteo

Pavia, Italy

Location

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Roma, Italy

Location

Ao Citta' Della Salute E Della Scienza D- Osp.S. Giov.Battista Molinette

Torino, Italy

Location

Asst Dei Sette Laghi

Varese, Italy

Location

Istituto Oncologico della Svizzera Italiana (IOSI)

Bellinzona, Switzerland

Location

Luzerner Kantonsspital

Lucerne, Switzerland

Location

Klinik für Hämatologie

Zurich, Switzerland

Location

Related Publications (1)

• Tedeschi A, Frustaci AM, Condoluci A, Coscia M, Chiarle R, Zinzani PL, Motta M, Gaidano G, Quaresmini G, Scarfo L, Catania G, Deodato M, Jones R, Tabanelli V, Griggio V, Stussi G, Calleri A, Pini K, Cairoli R, Zenz T, Signori A, Zucca E, Rossi D, Montillo M. Atezolizumab, venetoclax, and obinutuzumab combination in Richter transformation diffuse large B-cell lymphoma (MOLTO): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2024 Oct;25(10):1298-1309. doi: 10.1016/S1470-2045(24)00396-6. Epub 2024 Sep 10.

  PMID: 39270702 DERIVED

MeSH Terms

Interventions

obinutuzumab; atezolizumab; venetoclax

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 23, 2019
• First Posted: September 10, 2019
• Study Start: October 4, 2019
• Primary Completion (Estimated): September 1, 2026
• Study Completion (Estimated): December 1, 2026
• Last Updated: May 28, 2024

Record last verified: 2024-05

Data Sharing

• IPD Sharing: Will not share

Locations

IT (14); CH (3)