Immuno-Oncology Drugs Elotuzumab, Anti-LAG-3 and Anti-TIGIT

Sponsor

Multiple Myeloma Research Consortium (Other)

Overall Status

Recruiting

CT.gov ID

NCT04150965

Collaborator

Bristol-Myers Squibb (Industry), Emory University (Other), Washington University School of Medicine (Other), Beth Israel Deaconess Medical Center (Other), Dana-Farber Cancer Institute (Other), Wake Forest University Health Sciences (Other), Memorial Sloan Kettering Cancer Center (Other), Icahn School of Medicine at Mount Sinai (Other), University of Texas (Other), Hackensack Meridian Health (Other), University of Michigan (Other)

104

Enrollment

Locations

Arms

53.6

Anticipated Duration (Months)

10.4

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This a Phase I/II randomized trial for patients with relapsed refractory Multiple Myeloma who have relapsed after treatment with prior therapies. The protocol is designed to evaluate two agents, Anti-LAG-3 and Anti-TIGIT, in order to understand their immunologic effects and safety both as single agents and in combination with pomalidomide and dexamethasone. In these arms, patients will be treated with either Anti-LAG-3 or Anti-TIGIT respectively for one cycle as single agent followed by the addition of pomalidomide and dexamethasone in combination for subsequent cycles.

A third arm allows patients to be treated with the FDA approved combination of elotuzumab plus pomalidomide and dexamethsone as a control. This arm will thus allow a concurrent standard of care comparator for the experimental arms.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma Relapsed Refractory Multiple Myeloma	Drug: Elotuzumab, pomalidomide, dexamethasone Drug: Anti-LAG-3 Drug: Anti-LAG-3 + Pomalidimide + Dexamethasone Drug: Anti-TIGIT Drug: Anti-TIGIT + Pomalidimide + Dexamethasone	Phase 1/Phase 2

Detailed Description

This study will enroll 104 patients to one of three treatment arms. The study is open to patients relapsing with refractory Multiple Myeloma who have:

received 3 prior lines of therapy
exposed to each of these 3 drug classes:
IMiD
proteasome inhibitors, and
anti-CD38 monoclonal antibody
relapsed and refractory are defined using the IMWG criteria:
disease that is non-responsive while on salvage therapy or progresses within 60 days of last therapy in patients who have achieved minimal response or better at some point previously to then progressing in their disease course.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

104 participants

Allocation:

Randomized

Intervention Model:

Sequential Assignment

Intervention Model Description:

Arm B: Anti-LAG-3 will treat patients with single agent for Cycle 1. In Cycle 2 and beyond Arm B combination Anti-LAG-3 + Pomalidomide + Dexamethasone. Arm C: Anti-TIGIT will treat patients with single agent for Cycle 1. In Cycle 2 and beyond Arm C combination Anti-TIGIT + Pomalidomide + Dexamethasone.Arm B: Anti-LAG-3 will treat patients with single agent for Cycle 1. In Cycle 2 and beyond Arm B combination Anti-LAG-3 + Pomalidomide + Dexamethasone. Arm C: Anti-TIGIT will treat patients with single agent for Cycle 1. In Cycle 2 and beyond Arm C combination Anti-TIGIT + Pomalidomide + Dexamethasone.

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase I/II Assessment of Combination Immuno-Oncology Drugs Elotuzumab, Anti-LAG-3 (BMS-986016) and Anti-TIGIT (BMS-986207)

Actual Study Start Date :

Jun 30, 2020

Anticipated Primary Completion Date :

Dec 18, 2024

Anticipated Study Completion Date :

Dec 18, 2024

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Arm A - Elotuzumab Patients receive Elotuzumab in combination with pomalidomide and dexamethasone. Arm A begings in Phase 2 portion.	Drug: Elotuzumab, pomalidomide, dexamethasone Study Patients with relapsed Multiple Myeloma will receive: Elotuzumab, Pomalidomide, and Dexamethasone Starting in Phase 2 Cycle 1 Day 1 forward. Each cycle is 28 days long. Other Names: Empliciti
Experimental: Arm B - Anti LAG-3 Single Agent Patients receive Anti-LAG-3 as a single agent for 1 Cycle in Phase 1 portion.	Drug: Anti-LAG-3 Patients with relapsed Multiple Myeloma will receive: Anti -LAG-3 single agent for Cycle 1. Each Cycle is 28 days Cycle 2 forward patients will receive Anti-LAG-3 in combination with pomalidomide and dexamethasone from Cycle 2 forward. Each cycle is 28 days long. Other Names: BMS-986016 Anti LAG-3 Relatlimab
Experimental: Arm B:Combination Anti LAG-3 +Pomalidomide+Dexamethasone Cycle 2 and beyond Patients receive Anti-LAG-3 in combination with pomalidomide and dexamethasone.	Drug: Anti-LAG-3 + Pomalidimide + Dexamethasone Patients with Relapsed & Refractory Multiple Myeloma will receive: Anti-LAG-3 in combination with pomalidomide and dexamethasone from Cycle 2 forward. Each cycle is 28 days. Other Names: BMS-986016 Anti-LAG-3, Pomalidomide, Dexamethasone
Experimental: Arm C - Anti-TIGIT Single Agent Patients receive Anti-TIGIT as a single agent for 1 Cycle in Phase 1 portion.	Drug: Anti-TIGIT Patients with relapsed Multiple Myeloma will receive: Anti -TIGIT single agent for Cycle 1. Each cycle is 28 days. Other Names: BMS-986207
Experimental: ARM C: Anti-TIGIT +Pomalidomide+Dexamethasone Cycle 2 and beyond Patients receive Anti-TIGIT in combination with pomalidomide and dexamethasone.	Drug: Anti-TIGIT + Pomalidimide + Dexamethasone Cycle 2 and beyond patients will receive Anti-TIGIT in combination with pomalidomide and dexamethasone from Cycle 2 forward. Each cycle is 28 days.. Other Names: BMS-986207

Outcome Measures

Primary Outcome Measures

Overall Response Rate [Patients will be evaluated monthly for response from the start of the study until the date of documented disease progression, assessed up to 18 months.]
The overall response rate of the drug combination, in each Arm for RRMM, which is defined as the proportion of subjects who achieved a response (≥ VGPR).
Frequency, type and grade of Adverse Events and Serious Adverse Events [Cycle 1 (28 days)]
Frequency, type and grade of Adverse Events and Serious Adverse Events during Cycle 1 of Single agent Arms B and C. In Combination for all Arms.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

18 years of age or greater.
Willing and able to provide informed consent
Patient has received at least 3 prior lines of therapy and must have received prior therapy including at least one drug from each drug class; IMiD, proteasome inhibitors, and anti-CD38 monoclonal antibody.
The following laboratory values obtained ≤ 14 days prior to initiation of therapy:
ANC ≥ 1000/ul (without growth factor support within 14 days of initiation of therapy)
Hgb ≥ 8 g/dl
PLT ≥ 75,000/ul (without transfusion support within 14 days of initiation of therapy)
Total bilirubin <1.5 x upper limit of normal (ULN) or if total bilirubin is ≥1.5 x ULN, the direct bilirubin must be ≤ 2.0 mg/dL (patients with Gilberts syndrome may have total bilirubin ≤3.0 x ULN
AST and ALT < 2.5x ULN
Creatinine Clearance ≥ 30 mL/min by Cockcroft Gault Equation
Measurable disease of MM as defined by at least ONE of the following:
Serum monoclonal protein ≥1.0 g by protein electrophoresis
≥200 mg of monoclonal protein in the urine on 24-hour electrophoresis
Serum immunoglobulin FLC ≥10 mg/dL AND abnormal serum immunoglobulin kappa to lambda FLC ratio.
Normal thyroid function, or stable on hormone supplementation per investigator assessment.
Eastern Cooperative Oncology Group (ECOG) Performance Status 0, 1, or 2.
Willingness to return to enrolling institution for follow-up.
Disease free of prior malignancies for ≥ 3 year with exception of currently treated basal cell, squamous cell carcinoma of the skin, carcinoma "insitu" of the cervix or breast, or prostate cancer not requiring therapy
Ability to understand the purpose and risks of the study and provide signed and dated ICF and authorization to use protected health information.
All study participants must be willing to be registered into, and comply with, the mandatory pomalidomide (POMALYST®) Risk Evaluation and Mitigation Strategy (REMS®) program and be willing to use contraception 28 days prior to pomalidomide treatment and continue until 120 days after the last dose of pomalidomide.
Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation. For patient's intolerant to aspirin or for high-risk patients with prior history of thromboembolic events, thromboprophylaxis with other anti-coagulants agents, including low molecular weight heparin, warfarin, or novel oral anticoagulants such as apixaban or rivaroxaban, is allowed.
All females of child bearing potential (FCBP)* must have a negative pregnancy test (urine or serum) documented ≤7 days prior to start of therapy with repeat pregnancy test on Day 1 of each cycle and at the EoT visit. Note: Additional pregnancy testing is required as a condition of the POMALYST REMS® program prior to and while on treatment and following the last dose of pomalidomide. FCBP must have 2 negative pregnancy tests prior to initiating pomalidomide treatment. The first test should be performed within 10-14 days prior to prescribing POMALYST and the second test within 24 hours prior to prescribing POMALYST therapy and then weekly during the first 4 weeks, then every 4 weeks thereafter in females with regular menstrual cycles, or every 2 weeks in females with irregular menstrual cycles. Protocol section 8.1 provides guidelines on the use and required time frames of contraception. NOTE: *A female of childbearing potential (FCBP) is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) 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).

Exclusion Criteria:

Patient is known to be human immunodeficiency virus (HIV) positive, Hepatitis B surface antigen-positive, Hep B PCR positive or active Hepatitis C infection
Pregnant or breast feeding females;
Any clinically significant, uncontrolled medical conditions including, but not limited to, myocardial infarction or stroke/transient ischemic attack within the past 6 months, uncontrolled angina within the past 3 months, symptomatic congestive heart failure, cardiac arrhythmia (such as ventricular tachycardia, ventricular fibrillation, or torsades de pointes), pericarditis, myocarditis, cardiomyopathy, requirement for supplemental oxygen;
Any psychiatric illness/social situations that, in the Investigator's opinion, would impose excessive risk to the patient or may interfere with compliance or interpretation of the study results;
QT interval corrected for heart rate using Fridericia's formula (QTcF) prolongation > 480 msec, except for right bundle branch block;
Ongoing or active infection, that requires systemic antibacterial, antiviral, or antifungal therapy < 7 days prior to the initiation of therapy
Inability to tolerate thromboprophylaxis ;
Known CNS involvement;
Known severe intolerance to steroid therapy (Grade 3 or above adverse event unresponsive to dose reduction and/or per investigators discretion);
History of autoimmune disease, requiring therapy including but not limited to systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Bell's palsy, Guillain-Barré syndrome, multiple sclerosis, vasculitis, glomerulonephritis, or suspected autoimmune disease. (Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, euthyroid with a history of Grave's disease (participants with suspected autoimmune thyroid disorders must be negative for thyroglobulin and thyroid peroxidase antibodies and thyroid stimulating Ig prior to the first dose of study drug), psoriasis not requiring systemic treatment, well controlled asthma and/or mild allergic rhinitis [seasonal allergies], or conditions not expected to recur in the absence of an external trigger);
NYHA Classification > Class 2;
Concurrent amyloidosis, plasma cell leukemia or POEMS syndrome [plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein (M-protein) and skin changes;
History of erythema multiforme or severe (≥ grade 3) hypersensitivity to prior IMiD's;
1. Anti-cancer therapy within the specified time frames prior to initiation of therapy: cytotoxic investigational agents, within 3 weeks (6 weeks for nitrosoureas), IMiDs, Proteosome inhibitors or corticosteroids within 2 weeks, investigational therapies within 14 days or 5 half-lives of the investigational drug, whichever is longer, and monoclonal antibodies within 4 weeks, bispecifics (antibodies) within 4 weeks, CAR-T within 4 weeks post infusion. Prednisone up to but no more than 10 mg orally q.d. or its equivalent for symptom management of comorbid conditions is permitted but dose should be stable for at least 7 days. Live vaccines within 30 days (The inactivated seasonal influenza vaccine can be given to patients before treatment and while on therapy without restriction). Shorter time lines may be considered in consultation with the PI;
Prior major surgery or radiation therapy within 4 weeks of initiation of therapy;
Prior therapy with Anti-TIGIT or Anti-LAG-3 ; Elotuzumab
Any > Grade 1 adverse reaction unresolved from previous treatments according to the NCI CTC AE v 5.0. The presence of alopecia or peripheral neuropathy ≤ Grade 2 without pain is allowed;
Previous allogeneic stem cell transplantation;
Immunosuppressive therapy in the last 2 months prior to initiation of therapy;
Autologous stem cell transplant if < 12 weeks from initiation of therapy;
History of idiopathic pulmonary fibrosis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.);
Cardiac Troponin T (cTnT) or I(cTnI)≥2×institutional ULN.
Subjects with cTnT or cTnI levels between > 1 to 2 × ULN will be permitted if repeat levels within 24 hours are ≤ 1 ULN
If cTnT or cTnI levels are >1 ULN at 24 hours, the subject may undergo a cardiac evaluation and be considered for treatment, following a discussion with the Principal Investigator.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Emory University	Atlanta	Georgia	United States	30322
2	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02115
3	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02115
4	University of Michigan	Ann Arbor	Michigan	United States	48109
5	Washington University School of Medicine Division of Medical Oncology	Saint Louis	Missouri	United States	63110
6	Hackensack Meridian Medical Center	Hackensack	New Jersey	United States	07601
7	Mount Sinai School of Medicine	New York	New York	United States	10029
8	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
9	Levine Cancer Institute	Charlotte	North Carolina	United States	28204
10	UT Southwestern Medical Center	Dallas	Texas	United States	75390