Clinical Trials /

PK,PD, Safety and Tolerability of Multiple Dose Regimens of MT-3724 With Lenalidomide for the Treatment of Patients With Relapsed/Refractory B-Cell Non-Hodgkin's Lymphoma (MT-3724_NHL_003)

NCT03645395

Description:

The purpose of this study is to evaluate the safety and tolerability of MT-3724 in combination with Lenalidomide in subjects with relapsed or refractory B-Cell NHL.

Related Conditions:
  • B-Cell Non-Hodgkin Lymphoma
  • Diffuse Large B-Cell Lymphoma
Recruiting Status:

Terminated

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: PK,PD, Safety and Tolerability of Multiple Dose Regimens of MT-3724 With Lenalidomide for the Treatment of Patients With Relapsed/Refractory B-Cell Non-Hodgkin's Lymphoma (MT-3724_NHL_003)
  • Official Title: A Phase 2a Open-label Study to Investigate Safety and Tolerability (Including the Maximum Tolerated Dose), Efficacy, Pharmacokinetics, Pharmacodynamics and Immunogenicity of MT-3724 in Combination With Lenalidomide in Subjects With Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: MT-3724_NHL_003
  • NCT ID: NCT03645395

Conditions

  • Non-hodgkin Lymphoma

Interventions

DrugSynonymsArms
MT-3724MT-3724 10 mcg/kg-LEN

Purpose

The purpose of this study is to evaluate the safety and tolerability of MT-3724 in combination with Lenalidomide in subjects with relapsed or refractory B-Cell NHL.

Detailed Description

      This is a multi-center, open-label two-part study evaluating the safety and tolerability of
      MT-3724 in combination with Lenalidomide in relapsed or refractory CD20 positive B-cell
      Lymphoma patients.

      Part 1: (MT-3724 Dose Escalation) Define the maximum tolerated dose (MTD) of MT-3724 in
      combination with standard treatment of Lenalidomide

      Part 2: (MTD Expansion Cohort) Confirm the safety and tolerability of the MTD of MT-3724 from
      Part 1 in the MTD Expansion Cohort, where MT-3724 will be given at the MTD in combination
      with Lenalidomide. In addition, the PK, PD, immunogenicity and tumor response at the MTD of
      MT-3724 in combination with Lenalidomide will be more thoroughly evaluated in Part 2.

      It is anticipated that up to 64 patients will be enrolled. Treatment will continue until
      disease progression, withdrawal of consent or any other reason.
    

Trial Arms

NameTypeDescriptionInterventions
MT-3724 10 mcg/kg-LENExperimentalMT-3724 10 mcg/kg/dose IV for 6 doses over 12 days (M-W-F X 2 weeks) of each 28 day cycle in combination with LEN. If the treatment with MT-3724 is continued beyond Cycle 2, then MT-3724 will be administered weekly (Day 1, 8, 15 and 22) of each 28-day cycle
  • MT-3724
MT-3724 25 mcg/kg-LEN 3x a weekExperimentalMT-3724 25 mcg/kg/dose IV for 6 doses over 12 days (M-W-F X 2 weeks) of each 28 day cycle in combination with LEN. If the treatment with MT-3724 is continued beyond Cycle 2, then MT-3724 will be administered weekly (Day 1, 8, 15 and 22) of each 28-day cycle
  • MT-3724
MT-3724 20 mcg/kg-LEN 3x a weekExperimentalMT-3724 20 mcg/kg/dose IV for 6 doses over 12 days (M-W-F X 2 weeks) of each 28 day cycle in combination with LEN. If the treatment with MT-3724 is continued beyond Cycle 2 , then MT-3724 will be administered weekly (Day 1, 8, 15 and 22) of each 28-day cycle
  • MT-3724
MT-3724 25 mcg/kg-LEN 2x a weekExperimentalMT-3724 25 mcg/kg dose IV for 4 doses (days 1, 5, 8 and 12 during cycles 1 and 2) of each 28 day cycle in combination with LEN and weekly during cycles 3 and beyond (days 1, 8, 15 and 22).
  • MT-3724
MT-3724 50 mcg/kg-LENExperimentalMT-3724 50 mcg/kg dose IV for 4 doses (days 1, 5, 8 and 12 during cycles 1 and 2) of each 28 day cycle in combination with LEN and weekly during cycles 3 and beyond (days 1, 8, 15 and 22).
  • MT-3724

Eligibility Criteria

        Inclusion Criteria:

        - Subjects must meet ALL the following criteria to be eligible for the study.

          1. Be adequately informed about the study and fully consent to participation as
             demonstrated by signing the written ICF before any screening procedure.

          2. Be aged ≥18 years years on the date of signing the informed consent form.

          3. Have relapsed or refractory CD20 positive B-cell NHL that, in the investigator's
             opinion, could benefit from MT-3724+LEN therapy. Subjects must have proof of CD20
             positive NHL either by:

               1. Historical biopsies (obtained with diagnosis of relapsed or refractory disease),
                  or

               2. Fresh biopsies.

                    -  Bone marrow biopsy

                    -  Excisional lymph node biopsy

               3. Core biopsy of any involved organ; all are acceptable methods; FNA not acceptable

          4. All subtypes of B-cell NHL may be considered for Part 1 (MT-3724 dose escalation).
             Only histologically documented DLBCL (including mixed histology) may be considered for
             Part 2 (MTD expansion cohort).

          5. Have received all available approved therapies for NHL, one of which should be
             anti-CD20 based therapy.

               1. Subjects whose prior therapy includes chimeric antigen receptor t-cell (CAR-T)
                  cell therapy are eligible.

               2. Subjects who underwent stem cell transplant (SCT) >100 days for autologous SCT or
                  >180 days for allogeneic SCT before study drug administration and exhibited a
                  full hematological recovery (consistent with the existing inclusion criteria
                  requirements and without PRBC or platelet transfusions within 2 weeks of C1D1)
                  prior to relapse are eligible.

          6. Have bi-dimensionally measurable disease by Lugano Classification for NHL:

               1. >1.5 cm LDi for lymph nodes

               2. >1.0 cm LDi for extra nodal disease.

          7. Eastern Cooperative Oncology Group (ECOG) performance status of ≤2

          8. Have adequate bone marrow function, as determined by all the following:

               1. Absolute neutrophil count (ANC) ≥1,000/mm³

               2. Platelet count ≥50,000 mm³

               3. Hemoglobin ≥8g/dL

          9. Have adequate kidney function, creatinine clearance (CLcr) to be ≥50mL/min either
             measured or assessed by using the Cockcroft-Gault formula.

             a. At the investigator's discretion, the eGFR result ≤50 mL/min may be verified by
             measurement of CLcr based on the 24-hour urine collection. Subjects with CLcr ≥50
             mL/min will be eligible irrespective of the eGFR result.

         10. Have adequate hepatic function, as determined by:

               1. Total bilirubin ≤1.5 x upper limit normal (ULN), or direct bilirubin ≤1.5 x ULN
                  for subjects with elevated total bilirubin secondary to Gilbert's Syndrome) and

               2. Aspartate aminotransferase (AST) ≤3 x ULN (or ≤5 x ULN if liver involvement) and

               3. Alanine aminotransferase (ALT) ≤3 x ULN (or ≤5 x ULN if liver involvement)

         11. Have adequate coagulation, as determined by:

               1. International Normalized Ration (INR) or Prothrombin Time (PT) ≤1.5 x ULN (unless
                  on therapeutic anticoagulants)

               2. Activated partial thromboplastin time (aPTT) ≤1.5 x ULN (unless on therapeutic
                  anticoagulants)

         12. Albumin ≥ 3.0 g/dL

         13. Women of reproductive potential must have a negative pregnancy test on 2 occasions
             during the screening period (within 10-14 days and within 24 hours before the start of
             treatment). Women not of reproductive potential are female subjects who are
             postmenopausal(>1 year since last menstrual cycle) or permanently sterilized (e.g.,
             hysterectomy, bilateral salpingectomy).

         14. Males must agree to always use a latex or synthetic condom during any sexual contact
             with females of reproductive potential while taking LEN and for up to 4 weeks after
             discontinuing LEN, even if they have undergone a successful vasectomy. Male subjects
             taking LEN must not donate sperm.

         15. Subjects of reproductive potential and their partners must agree to either to abstain
             continuously from heterosexual intercourse or to use 2 methods of reliable birth
             control simultaneously to begin 4 weeks prior to initiating treatment with LEN until
             28 days after the last dose of MT-3724 or LEN. The investigator or a designated
             associate should advise the subject how to achieve adequate contraception. The
             following birth control methods may be considered: one highly effective form of
             contraception - tubal ligation, intrauterine device (IUD), hormonal (birth control
             pills, injections, hormonal patches, vaginal rings, or implants), or partner's
             vasectomy, and one additional effective contraceptive method - male latex or synthetic
             condom, diaphragm, or cervical cap.

         16. Subjects must have a life expectancy of >3 months from the start of treatment.

        Exclusion Criteria:

          -  Subjects who meet any of the following criteria must be excluded from the study.

        Medical and surgical history

          1. History or current evidence of neoplastic disease that is histologically distinct from
             NHL, except cervical carcinoma in situ, superficial noninvasive bladder tumors,
             curatively treated Stage I-II non-melanoma skin cancer. Subjects with prior,
             curatively treated cancer >2 years ago before the start of treatment can be enrolled.

          2. Current evidence of new or growing brain or spinal metastases during screening.
             Subjects with known brain or spinal metastases may be eligible if they:

               1. Had radiotherapy or another appropriate therapy for the brain or spinal
                  metastases; concurrent prophylactic treatment is allowed.

               2. Neurological symptoms must be stable and no worse than grade 2

               3. Have evidence of stable brain or spinal disease on computer topography (CT) or
                  magnetic resonance imaging (MRI) scan obtained within 4 weeks of signing the ICF
                  and compared with prior imaging results.

               4. Do not require chronic steroid therapy, or if applicable, have been stable on
                  steroid dose of no more than prednisone 20mg/day or equivalent by C1D1.

          3. Current evidence of Graft versus Host Disease.

          4. Current evidence of Common Terminology Criteria for Adverse Events (CTCAE) Grade >1
             toxicity (before the start of treatment, except for hair loss, and those Grade 2
             toxicities listed as permitted in other eligibility criteria).

          5. Current evidence of incomplete recovery from surgery or radiotherapy before the start
             of treatment, or planned surgery or radiotherapy at any time during the study until
             the EoT Visit, except minor elective interventions deemed acceptable by the
             investigator.

          6. Current evidence of significant (CTCAE Grade ≥2) infection or wound within 4 weeks
             before the start of treatment.

             a. Subjects with Grade 2 infection that has stabilized or improved with oral
             anti-infectives before the start of treatment may be eligible at the sponsor's
             discretion

          7. Current evidence of significant cardiovascular disease including, but not limited to
             the following conditions:

               1. Unstable angina (symptoms of angina at rest) or new-onset angina within ≤3 months
                  before the start of treatment.

               2. Arterial thrombosis or pulmonary embolism within ≤3 months before the start of
                  treatment.

               3. Myocardial infarction or stroke within ≤3 months before the start of treatment.

               4. Pericarditis (any CTCAE grade), pericardial effusion (CTCAE Grade ≥2), non
                  malignant pleural effusion (CTCAE Grade ≥2) or malignant pleural effusion (CTCAE
                  Grade ≥3).

               5. Congestive heart failure New York Heart Association (NYHA) Class III or IV at
                  screening or left ventricular ejection fraction (LVEF) <45%, assessed by Echo or
                  multiple-gated acquisition (MUGA) scan within 1 month before starting study
                  treatment. (inclusion of subjects with LVEF between 40%-45% should be discussed
                  and approved by the sponsor). Echo or MUGA scan performed within 6 months before
                  screening and at least 28 days after the last cancer therapy is acceptable
                  provided the subject has not received any potential cardiotoxic agents since
                  then.

               6. Cardiac arrhythmia requiring anti-arrhythmic therapy at Screening. Subjects
                  receiving digoxin, calcium channel blockers, or beta-adrenergic blockers are
                  eligible at the investigator's discretion after consultation with medical monitor
                  if the dose has been stable for ≥2 weeks before the start of treatment with
                  MT-3724. Subjects with sinus arrhythmia and infrequent premature ventricular
                  contractions are eligible at the investigator's discretion.

          8. QT interval corrected according to Fridericia's formula (QTcF) >480 ms, determined as
             the average from three QTcF values on the triplicate electrocardiogram (ECG) obtained
             at Screening.

          9. Current evidence of uncontrolled HIV, HBV or HCV at screening. Serology testing is not
             required if seronegativity is documented in the medical history and if there are no
             clinical signs suggestive of HIV or hepatitis infections, or suspected exposure. The
             following exceptions apply for subjects with positive viral serology:

               1. Subjects with HIV and an undetectable viral load and CD4+ T-cells counts ≥350
                  cells/microliter may be enrolled, but must be taking appropriate opportunistic
                  infection prophylaxis, if clinically relevant.

               2. Subjects with positive HBV serology are eligible if they have an undetectable
                  viral load and the subject will receive antiviral prophylaxis for potential HBV
                  reactivation-per institutional guidelines.

               3. Subjects with positive HCV serology are eligible if quantitative PCR for plasma
                  HCV RNA is below the lower limit of detection. Concurrent antiviral HCV treatment
                  per institutional guidelines is allowed.

         10. Women who are pregnant or breastfeeding.

         11. History or current evidence of hypersensitivity to any of the study drugs, or of
             current hypersensitivity requiring systemic steroids at doses >20 mg/day prednisone
             equivalent.

         12. History or current evidence of any other medical or psychiatric condition or addictive
             disorder, or laboratory abnormality that, in the opinion of the investigator, may
             increase the risks associated with study participation, or require treatments that may
             interfere with the conduct of the study or the interpretation of study results.

             Prior treatments

         13. Prior treatment with MT-3724.

         14. Received anti-CD20 monoclonal antibody (Mab) therapy within the following periods
             before the start of treatment

               1. Rituximab (Rituxan® RTX): 84 days; if a subject had received RTX within 37 Weeks
                  before the start of treatment, then a serum RTX level must be negative (<500
                  ng/mL) at screening.

               2. Obinutuzumab (Gazyva®): 184 days

               3. Ofatumumab (Arzerra®): 88 days

         15. Received therapy for NHL (except the anti-CD20 Mab therapies listed above and
             radioimmunoconjugates) within 4 weeks before the start of treatment.

         16. Any investigational drug treatment from 4 weeks or 5 half-lives of the agent before
             the start of treatment, whichever is longer, until the EoT Visit.

         17. Received radiotherapy to tumor lesions that would be chosen as target lesions
             (measurable disease) within 4 weeks before the start of treatment, unless the lesion
             exhibited objective progression between the radiotherapy and the screening according
             to the Lugano Classification for NHL.

             a. Palliative radiotherapy to non-target lesions may be permitted at the
             investigator's discretion after consultation with the medical monitor.

         18. Received any live vaccines within 4 weeks before of the start of treatment, unless the
             investigator believes the benefits outweigh the risks, after approval with the
             sponsor.

         19. Require use of systemic immune modulators during study treatment. a. Systemic immune
             modulators include but are not limited to systemic corticosteroids at doses >20 mg/day
             or prednisone equivalent, cyclosporine and tacrolimus.
      
Maximum Eligible Age:101 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Determine the tolerability of MT-3724 in combination with Lenalidomide for the Treatment of Patients With Relapsed/Refractory Non-Hodgkin's Lymphoma
Time Frame:Through study completion, anticipated to be approximately 1 year
Safety Issue:
Description:Incidence of AEs, including DLTs, inclusive of physical exam findings, laboratory abnormalities, and/or subject-reported symptoms

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Terminated
Lead Sponsor:Molecular Templates, Inc.

Last Updated

June 16, 2021