ObinutuzuMab AtezOlizumab and VenetocLax in RichTer transfOrmation (MOLTO)
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|ClinicalTrials.gov Identifier: NCT04082897|
Recruitment Status : Not yet recruiting
First Posted : September 10, 2019
Last Update Posted : September 10, 2019
|Condition or disease||Intervention/treatment||Phase|
|CLL Transformation||Drug: Obinutuzumab 25 MG/ML [Gazyva] Drug: Atezolizumab 60 MG/ML [Tecentriq] Drug: Venetoclax Oral Tablet||Phase 2|
This study is a multicenter, open-label, uncontrolled, phase II trial. Initial safety run phase is designed to establish the safety and tolerability of venetoclax, atezolizumab and obinutuzumab combination.
There is no dose-finding step. The doses of obinutuzumab and atezolizumab in lymphomas were previously clearly established in combination (Till BG et al. Blood 2015).
It has also been shown that in a balance between efficacy and toxicity, the recommended dose of venetoclax single-agent in Follicular Lymphoma (FL) and DLBCL was 800 mg daily (Davids MS et al. JCO 2017 ). The investigators chose the lower dose level (400 mg) for this study, also corresponding to the registered one for patients with CLL, in association with two other drugs. Nine patients having achieved 9 weeks (=3 cycles) of treatment (6 doses of obinutuzumab, 3 doses of atezolizumab, 7 weeks of venetoclax) or having discontinued treatment within the first 9 weeks of treatment will be enrolled in this cohort for safety profile. If one of these 9 patients prematurely discontinue at least one of study drugs for a reason other than safety (e.g. for disease progression), he/she will be replaced.
All AEs occurring during the course of the study will be captured, regardless of their intensity / grading. Grading of AEs will be completed according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTC-AE), version 4.0. Based on known safety profile of the 3 drugs, some adverse events of special interest will be assessed. During the initial safety run phase, all haematological toxicities and immune-related toxicities whatever the grade, and grade ≥ 2 for other toxicities will be monitored and, in this case, safety review meeting will be organized with Independent Data Monitoring Committee (IDMC) members. In case of more than 3 non-infective and non-hematologic grade ≥4 adverse events in the initial safety run cohort that according to the experience of the investigators are considered related to the combination treatment, inclusions will be stopped and IDMC members will evaluate the possibility of an early enrollment termination.
The treatment schedule applied to the initial safety run cohort will be employed for the remaining patients.
The 9 patients from the safety run will be included in the efficacy analysis. A response evaluation according with Lugano criteria for aggressive lymphomas (Cheson et al. JCO 2014) will be performed at the end of the sixth cycle to define treatment efficacy and, in case of achievement of 16 responses, treatment will be considered successful.
The planned enrollment for this study is 28 patients.
Patients will receive 35 cycles of treatment:
- From cycle 1 to cycle 8 patients will receive a combination of obinutuzumab, atezolizumab and venetoclax
- From cycle 9 to cycle 18 patients will receive atezolizumab and venetoclax
- From cycle 19 to cycle 35 patients will receive venetoclax monotherapy.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||28 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Multi-Center, Open Label, Uncontrolled, Phase II Clinical Trial Evaluating the Safety and Efficacy of Venetoclax in Combination With Atezolizumab and Obinutuzumab in Richter Transformation of CLL|
|Estimated Study Start Date :||September 2019|
|Estimated Primary Completion Date :||September 2026|
|Estimated Study Completion Date :||December 2026|
Experimental: Combination of Obinutuzumab, Atezolizumab and Venetoclax
Obinutuzumab will be administered iv from cycle 1 to cycle 8 :
Atezolizumab will be administered iv at 1.200 mg fixed dose from C1 to C18:
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]
Obinutuzumab will be administered from C1 to C8
Drug: Atezolizumab 60 MG/ML [Tecentriq]
Atezolizumab will be administered iv from C1 to C18
Drug: Venetoclax Oral Tablet
Venetoclax will be administered from day 15 cycle 1) until day 21 of cycle 35
- Efficacy of the combination venetoclax, obinutuzumab and atezolizumab in terms of Overall Response Rate (ORR) [ Time Frame: First 6 cycles of therapy (each cycle is 21 days) ]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).
- Safety (Incidence of Treatment-Emergent Adverse Events as assessed by NCI-CTCAE v4.0) of the combination venetoclax, obinutuzumab and atezolizumab [ Time Frame: During the entire study duration (estimated to be 7 years) ]Incidence of Adverse Events (AE) and Serious Adverse Events (SAE) as measured per NCI-CTCAE v4.0;
- Efficacy assessed by CRR of the combination venetoclax, obinutuzumab and atezolizumab [ Time Frame: During the entire study duration (estimated to be 7 years) ]Assessment of the efficacy of the combination of obinutuzumab, atezolizumab and venetoclax with respect to Complete Remission Rate (CRR) defined as best response of CR
- Efficacy assessed by DoR of the combination venetoclax, obinutuzumab and atezolizumab [ Time Frame: During the entire study duration (estimated to be 7 years) ]Assessment of the efficacy of the combination of obinutuzumab, atezolizumab and venetoclax with respect to Duration of Response (DoR) defined as Time from first CR or PR to progressive disease (PD) or death
- Efficacy assessed by PFS of the combination venetoclax, obinutuzumab and atezolizumab [ Time Frame: During the entire study duration (estimated to be 7 years) ]Assessment of the efficacy of the combination of obinutuzumab, atezolizumab and venetoclax with respect to Progression Free Survival (PFS) defined as the time from enrolment to the first occurrence of disease progression or death, as determined by the investigator
- Efficacy assessed by OS of the combination venetoclax, obinutuzumab and atezolizumab [ Time Frame: During the entire study duration (estimated to be 7 years) ]Assessment of the efficacy of the combination of obinutuzumab, atezolizumab and venetoclax with respect to Overall Survival (OS) defined as the time from the enrolment to death from any cause.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04082897
|Contact: Marco Montillo, MDfirstname.lastname@example.org|
|Contact: Alessandra Tedeschi, MDemail@example.com|
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