A Clinical Trial Evaluating the Safety and Efficacy of Venetoclax in Combination with Atezolizumab and Obinutuzumab in Richter Transformation of Cronic Lymphocitic Leukemia

Overview

Sponsor-declared trial summary

Key facts

Sponsor

ASST Grande Ospedale Metropolitano Niguarda

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

8 Oct 2019 → 30 Nov 2025

Decision date (initial)

2024-11-04

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Hoffmann-La Roche Ltd

External identifiers

EU CT number

2024-516675-32-00

EudraCT number

2018-005028-40

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

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

Secondary objectives 2

1. Safety and tolerability of the combination venetoclax, obinutuzumab and atezolizumab.
2. Efficacy of the combination venetoclax, obinutuzumab and atezolizumab in terms of: o Complete response rate, defined as CRR o Duration of response DoR 4 o Progression free survival (PFS) o Overall survival (OS)

Conditions and MedDRA coding

Richter syndrome of chronic lymphocytic leukemia

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Ability to understand and the willingness to sign a written informed consent document
2. Signed Informed Consent
3. 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
4. Age greater than or equal to 18 years
5. ECOG performance status <= 2
6. 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)
7. 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;
8. Subjects with Gilbert's Syndrome or resolving autoimmunehemolytic anemia may have a bilirubin up to 3.0 × ULN and are still eligible
9. Negative pregnancy tests as verified by the investigator prior to starting any treatment
10. Contraception/ breastfeeding: For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use a contraceptive method with a failure rate of < 1% per year during the treatment period and for at least 30 days after the last dose of venetoclax, 5 months after the last dose of atezolizumab or 18 months after the last dose of obinutuzumab, whichever is longer A woman is considered to be of childbearing potential if she is post-menarchal, has not reached a postmenopausal state (>12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus).

Exclusion criteria 35

1. Prior treatment for Richter transformation.
2. Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.
3. Known bleeding disorders (eg, von Willebrand's disease) or hemophilia.
4. History of human immunodeficiency virus (HIV) or active hepatitis C virus (HCV) or active hepatitis B virus (HBV).
5. Any life-threatening illness, medical condition, or organ system dysfunction that, inthe investigator's opinion, could compromise the subject's safety or put the study outcomes at undue risk.
6. Patients with infections requiring IV treatment (Grade 3 or 4) within the last 2 months prior to enrolment.
7. Prior treatment with obinutuzumab anti PD-1 or PDL-1 antibodies.
8. Prior treatment with venetoclax.
9. Hypersensitivity to obinutuzumab, venetoclax or atezolizumab or their formulation excipients.
10. Patients with the Hodgkin variant transformation of CLL.
11. 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).
12. Prolymphocytic transformation.
13. Patients with a previous history of indolent B cell malignancies other than CLL.
14. 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: a) Patients with curatively treated basal or squamous cell carcinoma or stage 1 melanoma of the skin or in situ carcinoma of the cervix b) 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. c) Low-risk prostate cancer on active surveillance.
15. 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 Cycle 1, Day 1
16. Major surgery within 4 weeks of first dose of study drug.
17. Requires anticoagulation with vitamin K antagonists (e.g. phenprocoumon, warfarin)
18. Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or Class 2 or higher congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomization.
19. Unable to swallow capsules or malabsorption syndrome, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction at time of screening.
20. Breastfeeding or pregnant
21. Clinically significant history of liver disease, including autoimmune hepatitis, current alcohol abuse, or cirrhosis.
22. Presence of positive PCR for hepatitis B, hepatitis C or positive hepatitis B surface antigen (HbsAg). Patients who are positive for HCV antibody must be negative for HCV by polymerase chain reaction (PCR) to be eligible for study participation. Patients with occult or prior HBV infection (defined as positive total hepatitis B core antibody [HBcAb] and negative HBsAg) may be included if HBV DNA is undetectable. These patients must be willing to receive prophylactic lamivudine or entecavir and undergo monthly DNA testing during treatment and up to 6 months’ post treatment..
23. Patients with uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia.
24. History of active autoimmune disease.
25. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis per chest CT scan at screening. History of radiation pneumonitis in the radiation field (fibrosis) is allowed.
26. Concurrent systemic immunosuppressant therapy within 28 days of the first dose of study drug.
27. Corticosteroids are allowed, but must be dosed at prednisone 30 mg (or equivalent) or lower prior to the start of chemotherapy.
28. Male subject who is considering fathering a child or donating sperm during the study or for approximately 6 months after the last dose of study drugs.
29. Unwilling or unable to participate in all required study evaluations and procedures. Unable to understand the purpose and risks of the study and to provide a signed and dated informed consent form (ICF)
30. Patients receiving any other study agents
31. Patients with known CNS involvement
32. Concurrent administration of medications or foods that are strong inhibitors or inducers of CYP3A Concurrent administration of medications or foods that are strong inhibitors or inducers of CYP3A see Appendix 9.
33. Strong and moderate CYP3A inhibitors within 7 days prior to the first dose of study drug administration
34. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies, known sensitivity or allergy to murine products.
35. Unable to receive prophylactic treatment for pneumocystis, herpes simplex virus (HSV), and herpes zoster (VZV) at start of treatment

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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 RT to treatment (Hallek M et al. IwCLL Criteria Blood 2008).

Secondary endpoints 2

1. Incidence of adverse events (AE) and serious adverse event (SAE) as measured per NCICTCAE v4.0; significant laboratory abnormality and dose tolerability (dose modifications and discontinuation).
2. Assessment of the efficacy of the combination of obinutuzumab, atezolizumab and venetoclax with respect to: - Complete Remission Rate (CRR) - Duration of Response (DoR) - Progression Free Survival (PFS) - Overall Survival (OS).

Investigational products

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

Test 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

ASST Grande Ospedale Metropolitano Niguarda

Sponsor organisation

ASST Grande Ospedale Metropolitano Niguarda

Address

Piazza Dell'ospedale Maggiore 3

City

Milan

Postcode

20162

Country

Italy

Scientific contact point

Organisation

ASST Grande Ospedale Metropolitano Niguarda

Contact name

Anna Maria Frustaci

Public contact point

Organisation

ASST Grande Ospedale Metropolitano Niguarda

Contact name

Anna Maria Frustaci

Third parties 3

Locations

1 EU/EEA country · 7 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 5 files

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

Application history

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