A Study of MBG453 in Combination With Azacitidine and Venetoclax in AML Patients Unfit for Chemotherapy (STIMULUS-AML1)
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| ClinicalTrials.gov Identifier: NCT04150029 |
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Recruitment Status :
Active, not recruiting
First Posted : November 4, 2019
Last Update Posted : January 23, 2023
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Acute Myeloid Leukemia | Drug: MBG453 Drug: Venetoclax Drug: Azacitidine | Phase 2 |
The purpose of the current study is to assess clinical effects of MBG453 in combination with hypomethylating agents (HMA) (azacitidine or decitabine) in adult subjects with International Prognostic Scoring System (IPSS-R) intermediate, high, very high risk MDS.
The primary purpose of Part 1 (Safety Run-in) is to rule out excessive toxicity of MBG453, when administered in combination with azacitidine and venetoclax.
The primary purpose of the combined Part 1 and Part 2 (Safety run-in and Expansion Part) is to evaluate efficacy of MBG453, when administered in combination with azacitidine and venetoclax in adult patients with newly diagnosed AML, who are not suitable for treatment with intensive chemotherapy.
There will be one analysis of the CR rate, 7 months after the last randomized subject. PFS will not be tested at this time point.
A maximum of two analyses will be performed for PFS. A PFS interim analysis will be scheduled when approximately 81 PFS events (after 75% of the planned target PFS events with an option to stop for efficacy) have been documented, expected to occur approximately 28 months after the first subject randomized. If PFS is not statistically significant at the IA, the study will continue until the final PFS analysis.
The final PFS analysis will be performed after observing approximately 108 PFS events (or at the latest at 4 years after the last subject is randomized) expected to occur approximately 51 months after the first subject randomized.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 90 participants |
| Allocation: | N/A |
| Intervention Model: | Sequential Assignment |
| Intervention Model Description: | safety -run -in with escalating dose of MBG453 followed by expansion |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | A Phase II Multi-center, Single Arm, Safety and Efficacy Study of MBG453 in Combination With Azacitidine and Venetoclax for the Treatment of Acute Myeloid Leukemia (AML) in Adult Patients Unfit for Chemotherapy |
| Actual Study Start Date : | September 1, 2020 |
| Estimated Primary Completion Date : | March 13, 2026 |
| Estimated Study Completion Date : | March 13, 2026 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: MBG453+Venetoclax +Azacitidine
Patients will receive MBG453 in combination with Venetoclax and Azacitidine
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Drug: MBG453
Solution for intravenous infusion
Other Name: Sabatolimab Drug: Venetoclax Tablet for oral administration Drug: Azacitidine Solution for subcutaneous injection or intravenous infusion |
- Incidence of dose limiting toxicities (Safety run-in patients only) [ Time Frame: From Cycle 1 Day 8 to end of Cycle 2; Cycle =28 Days ]Assessment of tolerability of MBG in combination with venetoclax and azacitidine
- Percentage of subjects achieving complete remission (CR) [ Time Frame: at least 6 cycles from last patient first treatment up to 100 weeks (each cycle =28 Days) ]Assessing Complete Remission (CR) Rate (Safety run in (expansion dose Level only) + Expansion)
- Percentage of subjects achieving a complete remission (CR) or complete remission with incomplete hematologic blood count recovery (CRi) [ Time Frame: every 12 weeks (starting at week 5) for up to 48 months from last patient first treatment ]Assessing the durability of complete remission (CR) or complete remission with incomplete hematologic blood count recovery (CRi) rate by determining the relapse free survival (RFS) in participants who achieve complete response (CR)
- Time from date of first documented CR or CRi to the date of first documented relapse or death due to any cause [ Time Frame: every 12 weeks (starting at week 5) for up to 48 months from last patient first treatment ]Time to relapse from CR/CRi or death (relapse free survival), whichever occurs first
- Time from the date of the first documented CR to the date of first documented relapse or death due to any cause [ Time Frame: every 12 weeks (starting at week 5) for up to 48 months from last patient first treatment ]Assessing the durability of complete remission (CR) by determining the Relapse Free Survival (RFS) in subjects who achieved CR, whichever occurs first
- Time from start of treatment until death, relapse from CR, or treatment failure, whichever occurs first [ Time Frame: every 12 weeks (starting at week 5) for up to 48 months from last patient first treatment ]Assessing event free survival (EFS).
- Time from start of treatment to death due to any cause (overall survival) [ Time Frame: date of start of treatment to date of death due to any reason (for up to 48 months from last patient first treatment) ]Time to death due to any cause to assess overall survival
- Peak Serum Concentration (Cmax) MBG453 [ Time Frame: Cycle 1 Day 8 (end of infusion) and Cycle 3 Day 8 (end of infusion), cycle = 28 days ]Maximal concentration of MBG453
- Trough Serum Concentration (Cmin) MBG453 [ Time Frame: Day 8 of Cycle 1,2,3,6,9,12,18, 24 and through treatment completion, an average of 24 months ]Concentration of MBG453 prior to next dosing or after end of treatment
- Trough Plasma Concentration (Cmin) Venetoclax [ Time Frame: Day 8 of Cycle 1, 3 and 8 ; Cycle =28 days ]Trough concentration of venetoclax on treatment
- Anti-drug Antibody (ADA) prevalence at baseline [ Time Frame: prior to first dose of MGB453 on Cycle 1 Day 8 (cycle =28 Days) ]Immunogenicity to MBG453 prior to MBG453 exposure
- ADA prevalence on-treatment [ Time Frame: Throughout study until 150 day safety follow-up ]Immunogenicity to MBG453 on Treatment and after treatment
- Percentage of MRD-negative subjects in the full study population and in subjects achieving CR or CRi [ Time Frame: every 12 weeks (starting at week 5) for up to 48 months from last patient first treatment ]Rate of MRD-negative subjects
- Rate of subjects who achieve transfusion independence from baseline and while on treatment. [ Time Frame: from start of treatment up to 48 months from last patient first treatment ]Percentage of subjects who are not dependent on blood transfusions for more than 8 weeks will be determined and related to the total number of patients participating to report percentage
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Signed informed consent must be obtained prior to participation in the study.
- Age ≥ 18 years at the date of signing the informed consent form (ICF)
- Newly diagnosed with AML based on 2016 WHO classification (Arber et al 2016) and not suitable for intensive chemotherapy defined as: age ≥75, ECOG performance Status 2 or 3, or any of the following comomorbitities: severe cardiac comorbities (including congestive heart failure, LVEF ≤ 50%, chronic stable Angina) , pulmonary comorbidity (DLCO ≤ 65% or FEVI ≤ 65%). moderate hepatic impairment (with total Bilirubin >1.5 to 3x ULN) , renal impairment (eGFR≥ 30 ml/min/1.73m^2 to 45 30 ml/min/1.73m^2), or other comorbidity incompatible with intensive chemotherapy per Investigator assessement and approved by the Novartis Medical monitor)
- .Not planned for hematopoietic stem-cell transplantation (HSCT)
- .Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 , 2 or 3
Exclusion Criteria:
- Prior exposure to TIM-3 directed therapy
- History of severe hypersensitivity reactions to any ingredient of study drug(s) (azacitidine, venetoclax or MGB453) or monoclonal antibodies (mAbs) and/or their excipients
- Current use or use within 14 days prior to randomization of systemic, steroid therapy (> 10 mg/day prednisone or equivalent) or any immunosuppressive therapy. Topical, inhaled, nasal, ophthalmic steroids are allowed. Replacement therapy, steroids given in the context of a transfusion are allowed and not considered a form of systemic treatment.
- Previous treatment at any time, with any of the following antineoplastic agents, approved or investigational; checkpoint inhibitors, venetoclax and hypomethylating agents (HMAs) such as decitabine or azacitidine.
- Active autoimmune disease requiring systemic therapy (e.g.corticosteroids).
- Live vaccine administered within 30 Days prior to randomization
Other protocol-defined Inclusion/Exclusion may apply.
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): NCT04150029
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| Study Director: | Novartis Pharmaceuticals | Novartis Pharmaceuticals |
| Responsible Party: | Novartis Pharmaceuticals |
| ClinicalTrials.gov Identifier: | NCT04150029 |
| Other Study ID Numbers: |
CMBG453C12201 2019-000439-14 ( EudraCT Number ) |
| First Posted: | November 4, 2019 Key Record Dates |
| Last Update Posted: | January 23, 2023 |
| Last Verified: | January 2023 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Yes |
| Plan Description: | Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent expert panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data is currently available according to the process described on www.clinicalstudydatarequest.com. |
| URL: | https://www.clinicalstudydatarequest.com |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
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MBG453 Venetoclax Azacitidine Phase 2 |
AML Acute myeloid Leukemia Sabatolimab |
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Leukemia Leukemia, Myeloid Leukemia, Myeloid, Acute Neoplasms by Histologic Type Neoplasms Azacitidine |
Venetoclax Antimetabolites, Antineoplastic Antimetabolites Molecular Mechanisms of Pharmacological Action Antineoplastic Agents Enzyme Inhibitors |