The purpose of this study is to evaluate the safety and tolerability of MT-3724 in
combination with gemcitabine and oxaliplatin (GEMOX) in subjects with relapsed or refractory
B-Cell NHL.
This is a multi-center, open-label two-part study evaluating the safety and tolerability of
MT-3724 in combination with GEMOX in relapsed or refractory 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 GEMOX
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 GEMOX. In addition, the PK, PD, immunogenicity and tumor response at the MTD of MT-3724
in combination with GEMOX will be more thoroughly evaluated in Part 2.
MT-3724 will be administered as intravenous (IV) infusion over 1 hour. In C1, MT-3724
infusion should be administered on Days 1, 3, 5, 8, 10, 12, 15, 22, 29, and 36 of the 42-day
cycle.
In Cycle 2 and beyond, MT-3724 will be administered weekly on Days 1, 8, 15, and 22 of each
28-day cycle.
During the first 2 weeks of C1, no more than two MT-3724 doses can be administered on
consecutive days. If MT-3724 is administered on consecutive days, then at least 20 hours
(more than 5 half-lives of MT-3724 in plasma) must elapse between the start of the 2
infusions.
For Weeks 3 through 6 of C1 and for C2 and beyond, different dosing days within ± 2 days from
scheduled weekly doses may be selected at investigator's discretion.
Treatment -Gemcitabine 1000 mg/m2 will be administered as 30-minute IV infusion. In C1,
Gemcitabine will be administered on Day 16 and Day 30 of the 42-day cycle.
In Cycle 2 and beyond, Gemcitabine will be administered on Day 2 and Day 16 of each 28-day
cycle.
Treatment -Oxaliplatin 100 mg/m2 will be administered as 2-hour IV infusion after
Gemcitabine. In C1, Oxaliplatin will be administered on Day 16 and Day 30 of the 42-day
cycle.
In Cycle 2 and beyond, Oxaliplatin will be administered on Day 2 and Day 16 of each 28-day
cycle. Oxaliplatin infusion will start one hour after the start of Gemcitabine infusion
(unless a delay is warranted at the investigator's discretion).
Continued Treatment with MT-3724 in combination with GEMOX will continue for four cycles of
until death, disease progression, unacceptable toxicity, withdrawal of consent or another
reason for withdrawal.
After four cycles, the subjects who experience clinical benefit can continue MT-3724
treatment with additional cycles of 28 days each (either alone or in combination with GEMOX)
if supported by the investigator's assessment of the benefit-risk ratio, after consultation
with sponsor and Medical Monitor
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
