Venetoclax and Tocilizumab for the Treatment of Patients With Relapsed or Refractory t(11;14) Multiple Myeloma
- Conditions
- Recurrent Plasma Cell MyelomaRefractory Plasma Cell Myeloma
- Interventions
- Registration Number
- NCT05391750
- Lead Sponsor
- Emory University
- Brief Summary
This phase I trial finds out the best dose and side effects of venetoclax and tocilizumab in treating patients with t(11;14) multiple myeloma that has come back (relapsed) or does not respond to treatment (refractory). Venetoclax may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Tocilizumab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread. Tocilizumab is used to treat side effects from immune therapy in patients with myeloma. Giving venetoclax and tocilizumab may kill more cancer cells.
- Detailed Description
PRIMARY OBJECTIVE:
I. To determine the dose limiting toxicity (DLT), safety profile, and the recommended phase 2 dose (RPTD) of venetoclax and tocilizumab when administered in subjects with relapsed and recurrent (RR) multiple myeloma t(11;14) (MM).
SECONDARY OBJECTIVES:
I.To evaluate the preliminary efficacy data regarding the effect of venetoclax and tocilizumab by objective response rate per IMWG criteria.
II. To evaluate the effect of chronic tocilizumab administration on venetoclax exposure.
TERTIARY/EXPLORATORY OBJECTIVES:
I. To evaluate the preliminary efficacy data regarding the effect of venetoclax and tocilizumab by time to response (TTR), time to disease progression (TTP), duration of response (DOR), progression free survival (PFS) and overall survival (OS).
II. To measure the effect of IL6 receptor blockade on ex vivo venetoclax sensitivity.
III. To evaluate the cell populations in the bone marrow of responders versus non-responders as well as the effect of IL6 receptor blockade on those populations.
IV. To evaluate the expression of B cell markers on venetoclax sensitive myeloma.
V. To determine the expression of key BCL2 family members with and without IL6 receptor blockade.
VI. To correlate differences in somatic mutations, structural alterations, gene expression and chromatin accessibility with venetoclax response.
OUTLINE: This is a dose-escalation study of venetoclax and tocilizumab.
Patients receive tocilizumab intravenously (IV) on day -7 of cycle 1, and on day 1 of subsequent cycles. Patients also receive venetoclax orally (PO) on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 4 weeks, then every 6 months thereafter.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 72
Not provided
Subject exhibits evidence of other clinically significant uncontrolled condition(s), including, but not limited to:
- Acute infection within 14 days prior to first dose of study drug requiring antibiotic, antifungal, or antiviral therapy
- Diagnosis of fever and neutropenia within 1 week prior to first dose of study drug
Subject has a cardiovascular disability status of New York Heart Association class >= 3
Subject has a significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, cardiovascular or hepatic disease within the last 6 months that, in the opinion of the investigator, would adversely affect his/her participation in the study
Subject has a history of other active malignancies other than multiple myeloma within the past 3 years prior to study entry, with the following exceptions:
- Adequately treated in situ carcinoma of the cervix uteri,
- Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin,
- Localized prostate cancer Gleason grade 6 or lower AND with stable prostate specific antigen (PSA) levels off treatment
- Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent
Known human immunodeficiency viral (HIV) infection
Active hepatitis B or C infection based on screening blood testing
Subject is receiving other ongoing anti-myeloma therapy
Subject has received any of the following within 7 days prior to the first dose of study drug:
- Strong or moderate CYP3A inhibitors, or
- Strong or moderate CYP3A inducers
Subject has received any of the following within 14 days prior to the first dose of study drug or has not recovered to less than a grade 2 clinically significant adverse effect(s)/toxicity(s) of the previous therapy: any anti-myeloma therapy including chemotherapy, radiotherapy, or investigational therapy, including targeted small molecule agents
Subject has received prior treatment with a BCL-2 family inhibitor
Subject is pregnant, parturient, or breastfeeding; deprived of freedom by judicial or administrative decision; hospitalized and unable to provide consent, or otherwise unable to provide consent
Subject has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or star fruit within 3 days prior to the first dose of study drug
Subject has received immunization with live vaccine within 60 days of dosing
Recent corticosteroid therapy at a cumulative dose equivalent to > 140 mg of prednisone or a single dose equivalent to >= 40 mg of dexamethasone within 2 weeks prior to the first dose of study drug
Subject's decision to not divulge the race
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Treatment (venetoclax, tocilizumab) Tocilizumab Patients receive tocilizumab IV on day -7 of cycle 1, and on day 1 of subsequent cycles. Patients also receive venetoclax PO on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Treatment (venetoclax, tocilizumab) Venetoclax Patients receive tocilizumab IV on day -7 of cycle 1, and on day 1 of subsequent cycles. Patients also receive venetoclax PO on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
- Primary Outcome Measures
Name Time Method Maximum tolerated dose (MTD) Completion of cycle 1 (each cycle is 21 days) The MTD for each arm is selected based on isotonic regression27, using the shiny app BOINComb (http://www.trialdesign.org). The dose is selected as the MTD for which the isotonic estimate of the toxicity rate is closest to the target toxicity rate. If there are ties, the higher dose level is selected when the isotonic estimate is lower than the target toxicity rate; the lower dose level is selected when the isotonic estimate is greater than or equal to the target toxicity rate.
- Secondary Outcome Measures
Name Time Method Overall response rate (ORR) Up to 5 years ORR will be calculated with an exact 95% confidence interval (CI) for each arm, using the Clopper-Pearson method.
Incidence of adverse events (AEs) Up to 30 days post-treatment AEs, related AEs, serious (S)AEs, related SAEs, and AEs leading to interruptions and/or discontinuation of study drug will be analyzed descriptively, using frequencies and percentages.
Complete response rate Up to 5 years Complete response rate will be calculated with an exact 95% CI for each arm, using the Clopper-Pearson method.
Duration of response (DOR) From date of treatment response to date of disease progression, assessed up to 5 years Median DOR will be reported, along with the 25th and 75th percentiles.
Progression-free survival (PFS) From date of receipt of study treatment to date of disease progression or death from any cause, where those alive without are censored at date of last follow-up, assessed up to 5 years PFS will be estimated using the Kaplan-Meier method. Median PFS will be reported, along with a 95% confidence interval estimated using the Brookmeyer-Crowley method.
Time to response (TTR) From date of receipt of study treatment to date of treatment response, where those not responding are censored at date of last follow-up or death from any cause, assessed up to 5 years TTR will be estimated using the Kaplan-Meier method. Median TTR will be reported, along with a 95% confidence interval estimated using the Brookmeyer-Crowley method.
Overall survival (OS) From date of receipt of study treatment to date of death from any cause, where those alive without are censored at date of last follow-up, assessed up to 5 years OS will be estimated using the Kaplan-Meier method. Median OS will be reported, along with a 95% confidence interval estimated using the Brookmeyer-Crowley method.
Time to disease progression (TTP) From date of receipt of study treatment to date of disease progression, where those not progressing or have died are censored at date of last follow-up or death from any cause, assessed up to 5 years TTP will be estimated using the Kaplan-Meier method. Median TTP will be reported, along with a 95% confidence interval estimated using the Brookmeyer-Crowley method.
Trial Locations
- Locations (1)
Emory University Hospital/Winship Cancer Institute
🇺🇸Atlanta, Georgia, United States