Clinical trial NCT04150965: Immuno-Oncology Drugs Elotuzumab, Anti-LAG-3 and Anti-TIGIT
Official title: A Phase I/II Assessment of Combination Immuno-Oncology Drugs Elotuzumab, Anti-LAG-3 (BMS-986016) and Anti-TIGIT (BMS-986207)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Multiple Myeloma
Relapsed Refractory Multiple Myeloma
Keywords: Multiple Myeloma
Relapsed
Refractory
MM
Multiple Myeloma Research Consortium
Multiple Myeloma Research Foundation
MMRC
MMRF
Lead sponsor: Multiple Myeloma Research Consortium
Sponsor class: NETWORK
Collaborators: name: Bristol-Myers Squibb
name: Emory University
name: Washington University School of Medicine
name: Beth Israel Deaconess Medical Center
name: Dana-Farber Cancer Institute
name: Wake Forest University Health Sciences
name: Memorial Sloan Kettering Cancer Center
name: Icahn School of Medicine at Mount Sinai
name: University of Texas
name: Hackensack Meridian Health
name: University of Michigan
First posted: 2019-11-05
Enrollment: 14
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: The trial is designed for patients with functionally high-risk MM (early relapse after initial therapy as defined above), who will be assigned to a targeted agent in the presence of an actionable mutation or an agent in the absence of an actionable genetic alteration, both in combination with a common backbone. This is a MMRC Sponsored multicenter, open label Phase 1/2 study of several different drugs in patients with relapsed myeloma, with treatment assignment guided by genomic studies.
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: Inclusion Criteria:

1. 18 years of age or greater.
2. Willing and able to provide informed consent
3. 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.
4. The following laboratory values obtained ≤ 14 days prior to initiation of therapy:

   1. ANC ≥ 1000/ul (without growth factor support within 14 days of initiation of therapy)
   2. Hgb ≥ 8 g/dl
   3. PLT ≥ 75,000/ul (without transfusion support within 14 days of initiation of therapy)
   4. 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
   5. AST and ALT \< 2.5x ULN
   6. Creatinine Clearance ≥ 30 mL/min by Cockcroft Gault Equation
5. Measurable disease of MM as defined by at least ONE of the following:

   1. Serum monoclonal protein ≥1.0 g by protein electrophoresis
   2. ≥200 mg of monoclonal protein in the urine on 24-hour electrophoresis
   3. Serum immunoglobulin FLC ≥10 mg/dL AND abnormal serum immunoglobulin kappa to lambda FLC ratio.
6. Normal thyroid function, or stable on hormone supplementation per investigator assessment.
7. Eastern Cooperative Oncology Group (ECOG) Performance Status 0, 1, or 2.
8. Willingness to return to enrolling institution for follow-up.
9. 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
10. Ability to understand the purpose and risks of the study and provide signed and dated ICF and authorization to use protected health information.
11. 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.
12. 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.
13. 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:

1. Patient is known to be human immunodeficiency virus (HIV) positive, Hepatitis B surface antigen-positive, Hep B PCR positive or active Hepatitis C infection
2. Pregnant or breast feeding females;
3. 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;
4. 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;
5. QT interval corrected for heart rate using Fridericia's formula (QTcF) prolongation \> 480 msec, except for right bundle branch block;
6. Ongoing or active infection, that requires systemic antibacterial, antiviral, or antifungal therapy \< 7 days prior to the initiation of therapy
7. Inability to tolerate thromboprophylaxis ;
8. Known CNS involvement;
9. Known severe intolerance to steroid therapy (Grade 3 or above adverse event unresponsive to dose reduction and/or per investigators discretion);
10. 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);
11. NYHA Classification \> Class 2;
12. Concurrent amyloidosis, plasma cell leukemia or POEMS syndrome \[plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein (M-protein) and skin changes;
13. History of erythema multiforme or severe (≥ grade 3) hypersensitivity to prior IMiD's;
14. 14. 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;
15. Prior major surgery or radiation therapy within 4 weeks of initiation of therapy;
16. Prior therapy with Anti-TIGIT or Anti-LAG-3 ; Elotuzumab
17. 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;
18. Previous allogeneic stem cell transplantation;
19. Immunosuppressive therapy in the last 2 months prior to initiation of therapy;
20. Autologous stem cell transplant if \< 12 weeks from initiation of therapy;
21. History of idiopathic pulmonary fibrosis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.);
22. Cardiac Troponin T (cTnT) or I(cTnI)≥2×institutional ULN.

    1. Subjects with cTnT or cTnI levels between \> 1 to 2 × ULN will be permitted if repeat levels within 24 hours are ≤ 1 ULN
    2. 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.

Primary outcomes:
measure: Overall Response Rate
timeFrame: 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.
measure: Frequency, type and grade of Adverse Events and Serious Adverse Events
timeFrame: Cycle 1 (28 days)
Secondary outcomes:
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Saint Louis
country: United States
facility: Washington University School of Medicine Division of Medical Oncology
state: Missouri
city: Hackensack
country: United States
facility: Hackensack Meridian Medical Center
state: New Jersey
city: New York
country: United States
facility: Mount Sinai School of Medicine
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Charlotte
country: United States
facility: Levine Cancer Institute
state: North Carolina
city: Dallas
country: United States
facility: UT Southwestern Medical Center
state: Texas
Study officials:
affiliation: Medical Monitor
name: Madhav V. Dhodapkar, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Chief Medical Officer
name: Hearn J. Cho, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
References: