A Study of TNB-383B in Participants With Relapsed or Refractory Multiple Myeloma

Study Overview
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Brief Summary
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This is a phase 1, open-label study evaluating the safety, clinical pharmacology and clinical activity of TNB-383B, a BCMA x CD3 T-cell engaging bispecific antibody, in participants with relapsed or refractory MM who have received at least 3 prior lines of therapy. The study consists of 4 portions, a monotherapy dose escalation (Arm A) and a monotherapy dose expansion (Arm B), Monotherapy once every 4 weeks (Q4W) dosing (Arm E), Monotherapy once every 3 weeks (Q3W) dosing (Arm F). Arm A will evaluate the safety, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) profiles of escalating doses of single-agent TNB-383B, administered Q3W, in approximately 73 participants. Once the maximum tolerated dose (MTD) or recommended phase 2 dose, (RP2D) is identified in Arm A, Arm B will be initiated to further characterize the safety, tolerability, PK and PD profiles of the MTD/RP2D 2 dose expansion arms of 48 participants each. Dose A will be evaluated as a monotherapy Q4W, in Arm E to further characterize the safety, tolerability, PK and PD profiles of the MTD/RP2D 2 dose expansion arms of 20 participants. Dose C will be evaluated as a monotherapy, in Arm F to further characterize the safety, tolerability, PK and PD profiles of the MTD/RP2D 2 dose expansion arms of 25 participants.

Official Title
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A Multicenter, Phase 1, Open-label, Dose-escalation and Expansion Study of TNB-383B, a Bispecific Antibody Targeting BCMA in Subjects With Relapsed or Refractory Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: TNB-383B


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has received three or more prior lines of therapy with exposure to a proteasome inhibitor (PI), an immunomodulatory imide (IMiD) and an anti-CD38 monoclonal antibody. Must have adequate bone marrow function as defined in the protocol. Must have an estimated glomerular filtration rate >= 30 mL/min as estimated by the Modification of Diet in Renal Disease formula. Must have total bilirubin <= 1.5 × upper limit of normal ([ULN]; except if the subject has a known diagnosis of Gilbert's syndrome, in which case bilirubin must be < 3 x ULN). Serum calcium (corrected for albumin) at or below the ULN range. Has Measurable Disease, defined as at least 1 of the following: Serum M-protein >= 0.5 g/dL (>= 5 g/L). Urine M-protein >= 200 mg / 24h. Serum free light chain (FLC) assay: Involved FLC level >= 10 mg/dl (>=100 mg/L) and an abnormal serum FLC ratio (< 0.26 or > 1.65). Has confirmed evidence of relapse/progression from the immediately prior MM therapy, or participant is relapsed/refractory to the immediately prior MM therapy. Consents to a fresh pretreatment bone marrow tumor biopsy or has adequate archival bone marrow tumor tissue that was collected within 6 months prior to screening and without intervening treatment. Exclusion Criteria: Has been diagnosed or treated for another malignancy within 3 years of enrollment, with the exception of basal cell or squamous cell carcinoma of the skin, in situ malignancy, low-risk prostate carcinoma after curative therapy, or complete resection/curative therapy of an advanced malignancy. History of central nervous system involvement by their myeloma. History of Grade >= 3 peripheral neuropathy. History of plasma cell leukemia, polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes (POEMS) syndrome, or amyloidosis. Has received another investigational drug within 21 days of enrollment. Has ever received BCMA-targeted therapy. Has received a autologous stem cell transplant within 12 weeks or an allogeneic stem cell transplant within 1 year of the first dose of study drug treatment. Has any medical or psychiatric condition which in the opinion of the investigator or study Medical Monitor places the participant at an unacceptably high risk for toxicities, could interfere with successful or safe delivery of therapy, or could interfere with evaluation of the investigational product or interpretation of participant safety or study results. Has received any therapy to treat cancer or undergone a major surgical procedure within 21 days, or within 5 half-lives of an anticancer drug, prior to the first dose of study treatment, whichever is shorter. Has known active infection Grade >= 2 requiring anti-infective treatment. Has a history of major cardiac abnormalities. Has unresolved adverse events as defined in the protocol.

Ages Eligible for Study
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Minimum Age: 18 Years

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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: Dose Escalation<br>Up to 15 cohorts of participants receiving sequentially ascending doses of TNB-383B are planned until maximum tolerated dose is reached or recommended phase 2 dose is identified. | Drug: TNB-383B<br>* Intravenous (IV) Injection<br>|
| Experimental: Arm B: Dose Expansion Dose A<br>An expansion cohort will be enrolled at the recommended phase 2 Dose A. | Drug: TNB-383B<br>* Intravenous (IV) Injection<br>|
| Experimental: Arm B: Dose Expansion Dose B<br>An expansion cohort will be enrolled at the recommended phase 2 Dose B. | Drug: TNB-383B<br>* Intravenous (IV) Injection<br>|
| Experimental: Arm E: Monotherapy Once Every 4 Weeks (Q4W)<br>An expansion cohort will be enrolled at the recommended phase 2 Dose A. | Drug: TNB-383B<br>* Intravenous (IV) Injection<br>|
| Experimental: Arm F: Monotherapy Dose C<br>An expansion cohort will be enrolled at the recommended phase 2 Dose C. | Drug: TNB-383B<br>* Intravenous (IV) Injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Dose-limiting toxicities (DLT) | A DLT is defined as a Treatment-emergent adverse event that is not unequivocally due to the participant's underlying malignancy or other extraneous cause. | Day 21 | 
| Number of Participants with Adverse Events (AEs) and/or Serious Adverse Events (SAEs) | An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. A serious adverse event (SAE) is an event that results in death, is life-threatening, requires or prolongs hospitalization, results in a congenital anomaly, persistent or significant disability/incapacity or is an important medical event that, based on medical judgment, may jeopardize the participant and may require medical or surgical intervention to prevent any of the outcomes listed above. | Up to 3 Years | 
| Maximum Observed Plasma Concentration of TNB-383B (Cmax) | Cmax of TNB-383B. | Week 12 | 
| Time to Cmax of TNB-383B (Tmax) | Time to maximum plasma concentration (Tmax) of TNB-383B. | Week 12 | 
| Area Under the Concentration Versus Time Curve from Time Zero to the Last Measurable Concentration (AUClast) | Area under the concentration versus time curve from time zero to the last measurable concentration of TNB-383B. | Week 12 | 
| Clearance (CL) of TNB-383B | Clearance is defined the volume of plasma cleared of the drug per unit time. | Week 12 | 
| Terminal Phase Elimination Rate Constant (Beta) of TNB-383B | Apparent terminal phase elimination rate constant of TNB-383B. | Week 12 | 
| Terminal Half-Life (t1/2) of TNB-383B | Terminal half-life (t1/2) of TNB-383B. | Week 12 | 
| Number of Participants with of Anti-drug Antibody (ADA) | The number of participants with anti-TNB-383B antibodies. | Up to Month 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | ORR is defined as confirmed Stringent complete response (sCR) + Complete response (CR) + very good partial response + partial response [PR]). | Up to Month 48 | 
| Percentage of Participants with Overall Survival (OS) | OS is defined as time from the first dose of TNB-383B to the date of death, from any cause. | Up to 48 Months | 
| Percentage of Participants with Progression-Free Survival (PFS) | Progression-free survival time is defined as the time from the first dose of TNB-383B to progression or death, whichever occurs first. | Up to 48 Months | 
| Time-to-Progression (TTP) | TTP is defined as the time from the first dose of TNB-383B to the date of the first documented disease progression. | Up to 48 Months | 
| Time-to-Response (TTR) | TTR is defined as the time from the first dose of TNB-383B to the date of the first assessment having documented the response. | Up to 48 Months | 
| Duration of Objective Response (DOR) | DOR is defined as the time from the initial objective response to disease progression or death, whichever occurs first. | Up to 48 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple Myeloma, TNB-383B