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.

Objectives

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 overall response rate (ORR) of venetoclax in combination with tocilizumab in relapsed and refractory myeloma (RRMM).
II. To determine the time to response (TTR), time to disease progression (TTP), duration of response (DOR), progression free survival (PFS) and overall survival (OS) with RRMM patients treated with venetoclax in combination with tocilizumab.
III. To evaluate the effect of chronic tocilizumab administration on venetoclax exposure.

TERTIARY/EXPLORATORY OBJECTIVES:
I. To measure the effect of IL6 receptor blockade on ex vivo venetoclax sensitivity.
II. To evaluate the cell populations in the bone marrow of responders versus [vs.] non-responders as well as the effect of IL6 receptor blockade on those populations.
III. To evaluate the expression of B cell markers on venetoclax sensitive myeloma.
IV. To determine the expression of key BCL2 family members and the effect of IL6 receptor blockade on this expression.
V. 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.

Eligibility

1. Subject must be >= 18 years of age
2. Subject has an Eastern Cooperative Oncology Group (ECOG) performance score of =< 2
3. Diagnosis of multiple myeloma that requires treatment and has been previously treated with: * >= 3 prior line of therapy. Have received treatment with a proteasome inhibitor, an immunomodulatory (IMiD) agent (e.g., thalidomide, lenalidomide, pomalidomide) and a CD38 monoclonal antibody * Have MM positive for t(11;14) translocation as determined by an analytically validated fluorescence in-situ hybridization (FISH) assay per the central laboratory testing
4. Subject must have had measurable disease at Screening, defined as any of the following: * Serum monoclonal protein >= 1.0 g/dL (>= 10 g/L) by protein electrophoresis, or * >= 200 mg of monoclonal protein in the urine on 24-hour electrophoresis, or * Serum immunoglobulin free light chain (FLC) >= 10 mg/dL provided serum FLC ratio is abnormal
5. Subjects with a history of autologous transplantation must have adequate peripheral blood counts as defined below, have recovered from any transplant related toxicity(s) and be > 100 days post-autologous transplant (prior to first dose of study drug)
6. Absolute neutrophil count (ANC) >= 1000/uL (Subject may use granulocyte colony-stimulating factor [G-CSF] to achieve ANC eligibility criteria)
7. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 1.5 x upper limit of normal range (ULN)
8. Calculated creatinine clearance >= 30 mL/min using a modified Cockcroft- Gault calculation or a 24-hour urine collection for creatinine clearance
9. Platelet count >= 30,000 cells/mm3 and independent of transfusion for 2 weeks
10. Hemoglobin >= 8.0 g/dL, subjects may receive blood transfusion to achieve hemoglobin eligibility criteria per investigator discretion
11. Total bilirubin =< 1.5 x ULN; subjects with Gilbert's syndrome may have bilirubin > 1.5 x ULN
12. If female, subject must be: * Postmenopausal defined as: ** Age > 55 years with no menses for 12 or more months without an alternative medical cause ** Age =< 55 years with no menses for 12 or more months without an alternative medical cause ** AND an follicle stimulating hormone (FSH) level > 40 IU/L. OR * Permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy) OR * A woman of childbearing potential (WOCP) practicing at least one protocol specified method of birth control starting at cycle 1 day 1 (or earlier) through at least 30 days after last dose of study drug
13. Females of childbearing potential (must have negative results for pregnancy test performed: * At screening, on a serum or urine sample obtained within 28 days prior to the first study drug administration, * Prior to dosing, on a urine sample obtained on the first day of study drug dosing, if it has been > 7 days since obtaining the serum pregnancy test results * Females of non-childbearing potential (either postmenopausal or permanently surgically sterile as defined above) at screening do not require pregnancy testing
14. Must voluntarily sign and date an informed consent, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study-specific procedures

Treatment Sites in Georgia