Clinical Trials /

PK,PD, Safety and Tolerability of Multiple Dose Regimens of MT-3724 With Lenalidomide for the Treatment of Patients With Relapsed/Refractory Diffuse Large 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:

Recruiting

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 Diffuse Large 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 MTD), 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
  • Refractory Diffuse Large B-Cell Lymphoma
  • Relapsed Diffuse Large B-Cell 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 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 for up to
      Six 28 day cycles (approximately 6 months)
    

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-LENExperimentalMT-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 50 mcg/kg-LENExperimentalMT-3724 50 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

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 informed consent form before any screening
                  procedure.

               2. Men or Women , age 18 years or older Have relapsed or refractory B-cell NHL that,
                  in the investigator's opinion, could benefit from MT-3724+LEN therapy.

               3. At least one histology documented relapse of NHL by:

                    1. Bone marrow biopsy (FNA is not acceptable)

                    2. Excisional lymph node biopsy or

                    3. Core biopsy of any involved organ (FNA not acceptable)

                    4. CD20-positive histology must have been confirmed at any time during NHL
                       disease course and documented in the medical history.

                    5. If no histology is available after any relapse the investigator can consult
                       the medical monitor to discuss if the patient can be included

               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 (expansion cohort)

               5. Have received all available approved therapies for NHL. Those subjects who are
                  ineligible for approved therapies in the opinion of the investigator, or have
                  refused such therapies, will be eligible.

               6. Have measurable disease by Lugano Classification for NHL (see Appendix 4):

                    1. >1.5 cm longest diameter (LDi) for lymph nodes

                    2. >1.0 cm LDi for extra nodal disease.

               7. Eastern Cooperative Oncology Group (ECOG) performance score 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

               9. Have adequate kidney function, assessed by the estimated glomerular filtration
                  rate (eGFR) ≥60 mL/min calculated by the CPK-EPI equation.

                  a. At the investigator's discretion, the eGFR result <60 mL/min may be verified
                  by measurement of creatinine clearance (CLcr) based on the 24-hour urine
                  collection. Subjects with CLcr ≥60 mL/min will be eligible irrespective of the
                  eGFR result.

              10. Have adequate hepatic function, as determined by:

                    1. Total bilirubin ≤1.5 x ULN, or ≤3 x ULN for subjects with Gilbert's
                       Syndrome) and

                    2. AST ≤3 x ULN and

                    3. ALT ≤3 x ULN

              11. Have adequate coagulation, as determined by:

                    1. INR or PT ≤1.5 x ULN

                    2. PTT ≤1.5 x ULN

              12. Have adequate serum albumin, as determined by:

                  a. 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 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 patients 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, 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.

        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 or any previous cancer
             curatively treated >2 years before the start of treatment.

          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

               2. Have no neurological symptoms (excluding Grade ≤2 neuropathy)

               3. Have stable brain or spinal disease on the CT or MRI scan within 1 month of
                  enrollment

               4. Do not require chronic steroid therapy

          3. History of allogeneic hematopoietic stem cell transplant within 180 days before the
             start of treatment.

          4. Current evidence of acute or chronic Graft versus Host Disease.

          5. Current evidence of CTCAE Grade >1 toxicity (except for hair loss, and those
             toxicities listed in other eligibility criteria) before the start of treatment.

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

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

          8. History or 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 (NYHA Class III or IV) at screening or LVEF <45%,
                  assessed by Echo or MUGA scan within 1 month before starting study treatment.
                  (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).

               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. Subjects
                  with sinus arrhythmia and infrequent premature ventricular contractions are
                  eligible at the investigator's discretion.

          9. QTcF (Fridericia) >480 ms, determined as the average from three QTcF values on the
             triplicate ECG obtained at screening.

         10. Current evidence of seropositive status for HIV, hepatitis B (positive for HBsAg or
             anti-HBsAg and anti-HBcAg antibodies) or hepatitis C (positive for anti-HCV antibody
             or HCV-RCV-RNA quantitation) as assessed by the applicable serology testing at
             screening.

               1. Serology testing is not required if seronegativity is documented in the medical
                  history and there are no clinical signs suggestive of HIV or hepatitis infection.

               2. Subjects with positive HBV serology are eligible if quantitative PCR for plasma
                  HBV-DNA is negative and the subject will be receiving prophylaxis for potential
                  HBV reactivation.

               3. Subjects with positive HCV serology are eligible if quantitative PCR for plasma
                  HCV RNA is negative.

         11. Women who are pregnant or breastfeeding.

         12. 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.

         13. 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

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

               1. Rituximab (Rituxan®): 84 days; if a subject had received rituximab within 37
                  Weeks before the start of treatment, then a serum rituximab 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) 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 is allowed at the investigator's
             discretion.

         18. Received any vaccines within 28 days of the start of treatment, or likely to require
             vaccines at any time from the start of treatment until 28 days after the last dose of
             MT-3724. Injectable flu vaccine (inactivated or recombinant) is permitted at the
             investigator's discretion.

         19. Received systemic immune modulators within 2 weeks before the start of treatment

               1. Systemic immune modulators include but are not limited to systemic
                  corticosteroids at doses >20 mg/day of prednisone equivalent, cyclosporine and
                  tacrolimus.

               2. The use of non-steroidal anti-inflammatory drugs (NSAIDs) is permitted
      
Maximum Eligible Age:101 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Tolerability as measured by number of subjects with dose limiting toxicities
Time Frame:28 days
Safety Issue:
Description:Evaluation of tolerability of MT-3724 measured by number of subjects with dose limiting toxicities (DLTs)

Secondary Outcome Measures

Measure:PK as measured by concentrations of free MT-3724 (Maximum Plasma Concentration [Cmax])
Time Frame:Dose 1 (Day 1) in Each 28-Day cycle up to 6 cycles, Dose 6 (Day 12) in Cycle 1 only
Safety Issue:
Description:Evaluation of the pharmacokinetic profile of MT-3724
Measure:PK as measured by concentrations of free MT-3724 (Area Under the Curve [AUC])
Time Frame:Dose 1 (Day 1) in Each 28-Day cycle up to 6 cycles, Dose 6 (Day 12) in Cycle 1 only
Safety Issue:
Description:Evaluation of the pharmacokinetic profile of MT-3724
Measure:PK as measured by concentrations of free MT-3724 (Time to reach maximum concentration after drug administration [Tmax])
Time Frame:Dose 1 (Day 1) in Each 28-Day cycle up to 6 cycles, Dose 6 (Day 12) in Cycle 1 only
Safety Issue:
Description:Evaluation of the pharmacokinetics profile of MT-3724
Measure:PD as measured by tumor response
Time Frame:Measured one at End of Treatment visit at approximately 6 months
Safety Issue:
Description:PD as measured by assessment of CD-20 positive status of DLBCL. Evaluation of the Pharmacodynamics profile of MT-3724 by fine needle aspirant of accessible peripheral LN as measured by IHC staining to determine CD 20 positive status of DLBCL in subject who exhibit progressive disease.
Measure:Immunogenicity as measured by MT-3724 [anti-drug antibody (ADA) titer and neutralizing antibody (NA)]
Time Frame:day 1 of each 28 day cycle:At approximately 1 month, 2 months, 3 months, 4 months, 5 months and 6 months
Safety Issue:
Description:Evaluation of the immunogenicity of MT-3724 {anti-drug antibody (ADA) titer and neutralizing antibody (NA) will be collected.Data for anti-drug antibody (ADA) against MT-3724 will be obtained as the positive or negative.
Measure:PD as measured by B-cell count in peripheral blood as determined by flow cytometry measured against MT-3724 serum concentrations at pre-specified time points
Time Frame:Day 1 in each Cycle, Day 12 of Cycle 1-Cycle 2, Day 15 of Cycle 3 -Cycle 6; each cycle is of 28 Days total of 6 cycles and overall 11 assessments
Safety Issue:
Description:Evaluation of the Pharmacodynamic profile of MT-3724
Measure:PD as measured by by immunophenotype in peripheral blood, as determined by flow cytometry measured against MT-3724 serum concentrations at pre-specified time points
Time Frame:Day 1 in each Cycle, day 12 of Cycle 1-Cycle 2, Day 15 of Cycle 3 -Cycle 6; each cycle is of 28 days
Safety Issue:
Description:Evaluation of the Pharmacodynamic profile of MT-3724
Measure:Tumor Response as measured by PET or CT scan
Time Frame:28 Days
Safety Issue:
Description:Tumor response to be assessed by the CT scan (PET or CT) of all the automatic regions involved with the measurable disease. Positron emission tomography-computed tomography (PET-CT) should be used in subjects with fluorodeoxyglucose (FDG)-avid tumor histology. Computed tomography (CT) or magnetic resonance imaging (MRI) should be used in subjects with tumor Histology of low or variable FDG avidity. Tumor response in subjects with FDG -avid tumor Histology will be determined using the 5 point scale (5 PS) according to the Lugano Classification for lymphoma (cheson 2014)adjusted according to LYRIC (lymphoma response to immunomudulatory therapy criteria)(Cheson 2016)The objective tumor response rate (ORR) at each time point to based on radiologist's measurement of all evaluable lesions.The ORR representing clinically significant clinical benefit in this study will comprise the Lugano score 1,2,or 3 or the CR or PR)

Details

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

Last Updated

September 5, 2019