PK,PD,Safety and Tolerability of Multiple Dose Regimens of MT-3724 With Gemcitabine and Oxaliplatin for the Treatment of Patients With Relapsed/Refractory Diffuse Large B Cell Non-Hodgkin's Lymphoma
Condition: Non-hodgkin Lymphoma,B Cell; Refractory Diffuse Large B-Cell Lymphoma; Relapsed Diffuse Large B-Cell Lymphoma
MeSH terms: Lymphoma; Lymphoma, Non-Hodgkin; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse
Intervention: MT-3724; Gemcitabine; Oxaliplatin
Intervention description: MT-3724 will be administered.; Gemcitabine will be administered.; Oxaliplatin will be administered.
Intervention MeSH terms: Gemcitabine; Oxaliplatin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 8.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      The purpose of this study is to evaluate the safety and tolerability of MT-3724 in
      combination with gemcitabine and oxaliplatin (GEMOX) in participants with relapsed or
      refractory B-Cell NHL.
    

Eligibility criteria:

        Inclusion Criteria:

          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. Be aged ≥18 years on the date of signing the informed consent form.

          3. Have relapsed or refractory B-cell NHL that, in the investigator's opinion, could
             benefit from MT-3724+GEMOX therapy. At least one histologically documented relapse of
             NHL, by:

               1. Bone marrow biopsy (FNA is not acceptable) or

               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 approved therapies for NHL that are applicable for the patient in
             the opinion of the treating physician.

               1. Patients refractory to treatment are eligible.

               2. Patient who have progressed following CAR T-cell therapy are also eligible.

          6. Have measurable disease by Lugano Classification for NHL

               1. >1.5 cm longest diameter (LDi) for lymph nodes

               2. >1 cm LDi for extranodal disease

          7. Have ECOG performance score of ≤2.

          8. Have adequate bone marrow function, as determined by:

               1. Absolute neutrophil count (ANC) ≥1,000/mm3 and

               2. Platelet count ≥50,000 mm³

          9. Have adequate kidney function, assessed by thecreatinine clearance (CLcr) to be ≥ 50
             mL/min either measured or estimated using the Cockcroft-Gault formula. .

             a. At the investigator's discretion,calculated estimated CLcr of < 50mL/min may be
             verified eGFR based on the 24-hour urine collection. Subjects with GFR ≥50 mL/min will
             be eligible irrespective of the estimated CLcr 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. Aspartate aminotransferase (AST) ≤3 x ULN (or ≤ 5.0 x ULN if liver involvement)
                  and

               3. Alanine aminotransferase (ALT) ≤3 x ULN (or ≤ 5.0 x ULN if liver involvement).

         11. Have adequate coagulation, as determined by:

               1. INR or PT ≤1.5 x ULN

               2. aPTT ≤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 during the
             screening period within 72 hours before the start of treatment. Women not of
             reproductive potential are female subjects who are postmenopausal or permanently
             sterilized (e.g., tubal occlusion, hysterectomy,bilateral salpingectomy).

         14. Subjects of reproductive potential and their partners must agree to either to abstain
             continuously from heterosexual intercourse or to use a reliable birth control method
             between signing the informed consent until 6 months following the last dose of MT-3724
             or GEMOX . The investigator or a designated associate should advise the subject how to
             achieve adequate contraception. The following birth control methods may be considered
             as adequate

               1. Condoms (male or female) with or without a spermicidal agent;

               2. Diaphragm or cervical cap with spermicide;

               3. Intrauterine device;

               4. Hormone-based contraception: Established use of oral, injected, or implanted
                  hormonal methods of contraception;

               5. True abstinence;

               6. Vasectomy is an acceptable method for a male subject or male partner of a female
                  subject.

        Exclusion criteria:

          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 other previous cancer
             curatively treated >2 years before the start of treatment.

          2. Current evidence of new or growing brain or spinal metastases during screening.

          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

          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. Patients with uncontrolled or severe cardiovascular disease, including myocardial
             infarct or unstable angina within 6 months prior to start of study treatment, New York
             Heart Association (NYHA) Class II or greater congestive heart failure, serious
             arrhythmias requiring medication for treatment, clinically significant pericardial
             disease, or cardiac amyloidosis may not be enrolled.

          9. Patients with a known history of drug abuse or any chronic neurologic, psychiatric,
             endocrine, metabolic, immunologic, hepatic or renal disease (including a history of
             hemolytic uremic syndrome) that in the opinion of the Investigator would adversely
             affect study participation.

         10. Patients with known active Hepatitis C, HIV or a present history of Hepatitis B

         11. Women who are pregnant or breastfeeding

         12. History or current evidence of hypersensitivity to any study drugs, or current
             evidence of hypersensitivity requiring systemic steroid doses ≥20 mg/day Prednisone
             equivalent

         13. Received any amount of anti-CD20 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 the screening period

               2. Obinutuzumab (Gazyva®): 184 days

               3. Ofatumumab (Arzerra®): 88 days

         14. Received therapy for NHL (except anti-CD20 Mab listed above) within 4 weeks before the
             start of treatment

         15. 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

         16. 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 after consultation with the Medical Monitor and sponsor.

         17. 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

         18. Received systemic immune modulators within 2 weeks before the start of treatment
             including but not limited to systemic corticosteroids >20 mg/day of prednisone
             equivalent, cyclosporine and tacrolimus. Corticosteroids for pre-medication and NSAIDs
             are permitted.

         19. Received any investigational drug treatment within 4 weeks or within 5 half-lives of
             the therapeutic agent before the start of treatment, whichever is longer, until EoT
             Visit