A Study of Venetoclax in Combination With Isatuximab and Dexamethasone for Relapsed/Refractory Multiple Myeloma

Study Overview
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Brief Summary
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A phase 2 study of venetoclax in combination with isatuximab and dexamethasone for relapsed/refractory multiple myeloma patients with t(11;14)

Detailed Description
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Despite recent advances in treating MM that have improved outcomes, patients with this B-cell malignancy inevitably become refractory to therapy, and thus, must rely on additional treatment options for long-term management of their disease. Venetoclax is an oral BCL-2 inhibitor which has been recently demonstrated to show clinical activity for the treatment of MM. The BCL-2 family of proteins are critical regulators of apoptosis which include both anti-apoptotic (e.g. BCL-2, MCL-1 and BCL-XL) and pro-apoptotic (e.g. BAK and BAX) elements. The upregulation of anti-apoptotic proteins has been reported for most cancers, but high BCL-2 levels have been especially prevalent in human lymphoid malignancies including chronic lymphocytic leukemia, for which venetoclax is currently indicated. BCL-2 is also overexpressed especially in the subset of MM patients with t(11;14) translocations, a cytogenetic abnormality found in approximately 20% of MM patients. Venetoclax as a single agent has been shown to induce apoptosis not only in human MM cell lines and primary MM tumor cell samples, but also specifically in RRMM patients. Clinical activity with single-agent venetoclax was mostly limited to those with (11;14) translocations, with 12 of 14 responses occurring among patients with that cytogenetic marker in the single-agent clinical trial of this BCL-2 inhibitor for patients with RRMM (#NCT01794520) as reported by Kumar et al.7 Resistance to venetoclax as a single agent has been shown to be mediated by MCL-1, with low BCL-2/MCL-1 ratios indicating resistance and high ratios indicating an increased sensitivity to this BCL-2 inhibitor. Furthermore, MCL-1 silencing was shown to heighten sensitivity to BCL-2 inhibitors, and MM xenograft models co-expressing BCL-2 with MCL-1 were resistant to venetoclax. The therapeutic landscape of MM has evolved even more with the discovery and validation of monoclonal antibodies in the treatment of MM. The first two monoclonal antibody-based therapies to show promising activity for treating MM patients were elotuzumab, which targets SLAMF7, and daratumumab, which targets CD38. A recent phase 1 study showed high response rates among RRMM patients with t(11;14) who were treated with daratumumab, dexamethasone and venetoclax.2 The most recent addition to the collection of the antibody-based therapies is a humanized IgG1 monoclonal antibody that binds selectively to a unique epitope on the human CD38 receptor, isatuximab (SAR-650984). A dose finding phase 2 trial of isatuximab as a single agent was well tolerated and showed clinical activity for heavily pre-treated patients with RRMM.3 Furthermore, a phase 1b study examining combination therapy consisting of isatuximab with lenalidomide and dexamethasone showed promising activity and good tolerability for heavily previously treated patients with RRMM. Based on the results of two phase 3 studies, the antibody has been FDA-approved in combination with pomalidomide or carfilzomib for treating RRMM patients. Notably, the investigators reported two cases of patients with RRMM who achieved rapid complete remissions to therapy with venetoclax at low doses (100 mg) in combination with bortezomib, dexamethasone and the anti-CD38 antibody daratumumab after failing multiple treatment regimens including bortezomib, dexamethasone and daratumumab. The investigators have recently reported on a larger retrospective study of RRMM patients receiving this combination. The response rate was 80% among those harboring the t(11;14) marker whereas it was only 31% among those lacking this chromosomal translocation. Responses were observed among patients who failed prior anti-CD38 antibody treatments. These results suggest that low doses of venetoclax may help overcome resistance to other anti-MM agents for the treatment of RRMM patients especially those with the t(11;14) chromosomal marker. Therefore, in this phase 2 trial, The investigators will evaluate the safety and efficacy of isatuximab, venetoclax and dexamethasone for treating patients with RRMM and show the t(11;14) marker.

Official Title
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A Phase 2 Study of Venetoclax in Combination With Isatuximab and Dexamethasone for Relapsed/Refractory Multiple Myeloma Patients With t(11;14)

Conditions
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Multiple Myeloma in Relapse, Multiple Myeloma, Refractory

Intervention / Treatment
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* Drug: Venetoclax


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Have a diagnosis of MM based on standard criteria as follows, both criteria a and b must be met: c. Clonal BM plasma cells ≥ 10% or biopsy-proven bony or extramedullary plasmacytoma d. Any or more of the following myeloma defining events: i. Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically: Hypercalcemia: serum calcium >2.75 mmol/L (>11 mg/dL) or >0.25 mmol/L (>1 mg/dL) higher than the upper limit of normal Renal insufficiency: creatinine clearance < 40mL/min or serum creatinine > 177 mmol/L (> 2mg/dL) Anemia: hemoglobin value of >2 g/dL below the lower limit of normal, or a hemoglobin value <10 g/dL Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT ii. Clonal BM plasma cell percentage > 60% iii. Involved: uninvolved SFLC ratio >100 (involved FLC level must be >100 mg/L) iv. > 1 focal lesion on MRI studies (at least 5 mm in size) 2. Show the t(11;14), confirmed by FISH or cytogenetic analysis , to be performed within 28 days prior to baseline. If performed more than 28 days prior, it should be repeated at the investigator's discretion 3. Absolute neutrophil count ≥ 1.5 x 10/L 4. Platelet count ≥ 75 x 109/L 5. Hemoglobin ≥ 8.0 g/dL within 21 days prior to enrollment. 6. Calculated or measured creatinine clearance (CrCl) of ≥ 30 mL/minute as calculated by Cockcroft-Gault method 7. Total bilirubin levels ≤ 2.0 mg/dL (normal levels) 8. AST (SGOT) and ALT (SGPT) ≤ 2 x ULN 9. Serum potassium within the normal range 10. Female of childbearing potential (FCBP)† must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10 - 14 days prior to and again within 24 hours of starting and must either commit to continued abstinence from heterosexual intercourse or use acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, and at least 28 days before she starts taking treatment drugs. FCBP must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a vasectomy. All subjects must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure. Contraception measures should be continued for 3 months following the treatment completion. A FCBP (female of childbearing potential) is a sexually mature woman who has not undergone a hysterectomy or bilateral oophorectomy; or has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months 11. Eastern Cooperative Oncology Group (ECOG) performance score less than or equal to 2 12. Participant must have received at least 3 lines of prior treatment for MM, including regimens that contained a proteasome inhibitor, lenalidomide, and glucocorticosteroids 13. Participant currently has documented progressive MM per IMWG criteria 14. Subject must be ≥ 18 years of age 15. Subject must voluntarily sign and date an informed consent Exclusion Criteria: Participant has a history of intolerability to any of the study drugs Participant has any of the following conditions: amyloidosis, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), known human immunodeficiency viral (HIV) infection, active hepatitis B or C infection based on blood screen tests, significant cardiovascular disease, including uncontrolled angina, severe or uncontrolled arrhythmia, recent myocardial infarction within 6 months of screening, or congestive heart failure New York Heart Association (NYHA) Class greater than or equal to 3, major surgery within 4 weeks prior to screening, acute infections requiring parenteral therapy (antibiotic, antifungal, or antiviral) within 14 days prior to screening, peripheral neuropathy greater than or equal to Grade 3 or greater than or equal to Grade 2 with pain within 2 weeks prior to screening, uncontrolled diabetes or uncontrolled hypertension within 14 days prior to screening, any other medical condition that, in the opinion of the Investigator, would adversely affect the participant's participation in the study Participant has a history of other active malignancies, including myelodysplastic syndrome (MDS), within the past 3 years prior to study entry, with the following exceptions: previous malignancy with no evidence of disease confined and surgically resected (or treated with other modalities) with curative intent and unlikely to impact survival during the duration of the study If participant had prior allogeneic stem cell transplant (SCT), participant has evidence of ongoing graft-versus-host disease (GvHD) Participants that are pregnant or breast feeding Participants with hypersensitivity to any study medications and/or their excipients Treatment with an anti-CD38 antibody (daratumumab or isatuximab) within the last six months Treatment with an anti-CD38 antibody (daratumumab or isatuximab), alone or in combination, without achieving a best response of at least a MR Treatment with venetoclax Participants that are refractory to anti-CD38 antibody treatment [i.e. disease progression (i.e., PD, per IMWG criteria) while receiving a CD38 MoAb or within 60 days of treatment (PD after 60 days after CD38 MoAb treatment is allowed)] Treatment with any of the following within 7 days prior to the first dose of study drug: Steroid therapy for anti-neoplastic intent Moderate or strong cytochrome P450 3A (CYP3A) inhibitors or inducers Administration or consumption of any of the following within 3 days prior to the first dose of study drug: d. Grapefruit or grapefruit products e. Seville oranges (including marmalade containing Seville oranges) f. Star fruit Additional prior and concomitant therapy excluded and cautionary medications: c. Excluded: i. Anticancer therapies including chemotherapy, radiotherapy, or other investigational therapy, including targeted small molecule agents: Excluded 5 half-lives prior to first dose and throughout venetoclax administration ii. Biologic agents (e.g., monoclonal antibodies) for anti-neoplastic intent: Excluded 28 days prior to first dose and throughout venetoclax administration d. Cautionary during the study: i. Strong and Moderate CYP3A inhibitors: Exclude during ramp-up phase and consider alternative medications. If subject requires use of these medications at the cohort designated dose, use with caution and reduce the venetoclax dose by 50% for moderate inhibitors and at least 75% for strong inhibitors during co-administration. After discontinuation of CYP3A inhibitor, wait for 2 to 3 days before venetoclax dose is increased back to the initial maintenance/target dose. ii. Strong and Moderate CYP3A inducers: Exclude during ramp-up phase and consider alternative medications. If subject requires use of these medications at the cohort designated dose, use with caution and contact AbbVie medical monitor for guidance. iii. Additional: Warfarin, P-gp substrates, BCRP substrates, OATP1B1/1B3 substrates, P-gp inhibitors, BCRP inhibitors
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: open-label<br>This is a Phase 2, multicenter, open-label study evaluating the safety and efficacy of venetoclax in combination with isatuximab and dexamethasone among RRMM patients who show the t(11;14) marker and currently show PD and have received at least 3 prior lines of therapy for multiple myeloma. All subjects in Dose Level 0 will receive 1) venetoclax, PO, at 400 mg every day (QD) on Days 1-28 of a 28-day cycle, 2) dexamethasone 40 mg IV, once weekly on Days 1, 8, 15, and 22 of a 28-day cycle where day 8 and 22 doses may be administered PO; and 3) isatuximab 10mg/kg, IV, on Days 1, 8, 15, and 22 of the first 28-day cycle, and then Days 1 and 15 during subsequent 28-day cycles. The primary safety analysis will focus on determining the DLTs for the study regimen, and occurrence of AEs throughout the study. | Drug: Venetoclax<br>* All subjects in Dose Level 0 will receive 1) venetoclax, PO, at 400 mg every day (QD) on Days 1-28 of a 28-day cycle, 2) dexamethasone 40 mg IV, once weekly on Days 1, 8, 15, and 22 of a 28-day cycle; and 3) isatuximab 10mg/kg, IV, on Days 1, 8, 15, and 22 of the first 28-day cycle, and then Days 1 and 15 during subsequent 28-day cycles.<br>* Other names: VENCLEXTA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Emergent Adverse Events [Safety] | Safety will be measured by counting the occurrence of adverse events throughout the study, graded via Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 criteria | [Time Frame: 54 months] | 
| Overall response rate (ORR) as a measure of efficacy | To assess the overall response rate (ORR = CR + VGPR + PR) | [Time Frame: 54 months] | 
| Clinical benefit rate (CBR) as a measure of efficacy | (CBR = CR + VGPR + PR + MR) | [Time Frame: 54 months] | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of the time to progression as a measure of efficacy (TTP) | Time to progression, defined as the time (in months) from the initiation of therapy to progressive disease.Time to progression, defined as the time (in months) from the initiation of therapy to progressive disease. | [Time Frame: 54 months] | 
| Progression Free Survival (PFS) | Progression-free survival will be measured in months as the time from initiation of therapy to progressive disease or death from any cause, whichever occurs first | [Time Frame: 54 months] | 
| Time to first response (TTFR) | Time to first response (TTFR), defined as the time from the initiation of therapy to the first evidence of confirmed clinical benefit defined as > MR including patients who achieved a CR, VGPR, PR, or MR | [Time Frame: 54 months] | 
| Duration of response (DOR) | Duration of response, defined as the time (in months) from the first response to progressive disease | [Time Frame: 54 months] | 
| Overall survival (OS) | Overall survival, defined as the time (in months) from initiation of therapy to death from any cause or last follow-up visit | [Time Frame: 54 months] | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple Myeloma, MM, RRMM, Relapsed/Refractory Multiple Myeloma