Safety, PD & Efficacy of MT-3724 for the Treatment of Patients With Relapsed or Refractory DLBCL

Safety, Pharmacodynamics and Efficacy of MT-3724 for the Treatment of Patients With Relapsed or Refractory DLBCL

The purpose of this study is to evaluate the safety and tolerability of MT-3724 in subjects with relapsed or refractory B-Cell NHL or relapsed and refractory CLL (Part 1 only) and relapsed and refractory DLBCL (Part 2 and Part 3). Part 3 evaluates the efficacy of MT-3724.

This is a three-part Phase 2 study

Part 1: (MT-3724 Dose Escalation) Define the maximum tolerated dose (MTD) of MT-3724 [Completed]

Part 2: (MTD Expansion Cohort) Confirm the safety and tolerability of the MTD of MT-3724 in the MTD Expansion Cohort.

Part 3: (Phase 2 MTD Expansion Cohort) Determine the efficacy of MT-3724 as monotherapy in subjects with relapsed or refractory DLBCL based on the overall response rate (ORR) by the revised Lugano Classification for Lymphoma adjusted according to LYRIC.

It is anticipated that up to 100 patients will be enrolled in Part 3. Treatment will continue for up to six 21 days cycles. If the subject exhibits SD, CR or PR after the end of Cycle 6 and the investigator determines that the benefit-risk ratio is favorable, then the treatment with MT-3724 may be continued after discussion with the sponsor.

Inclusion Criteria:

• Participants must be informed about the study and fully consent to participation as demonstrated by signing the written ICF before any screening procedure.

• Male and female participants >= 18 years of age at the time of informed consent.

• Participants must have relapsed or refractory Diffuse large B cell lymphoma (DLBCL) according to the Revised European American Lymphoma/World Health Organization classification. Participants must have proof of cluster of differentiation 20 plus (CD20+) DLBCL, based on either:

  • a. historical biopsies (obtained with diagnosis of relapsed or refractory disease), or
  • b. fresh biopsies
  • c. bone marrow biopsy, excisional lymph node biopsy, and core biopsy of any involved organ are all acceptable methods; Fine Needle Aspirate is not acceptable.

• Participants must have received at least 2 standard of care (SoC) regimens (including anti-CD20 antibody therapy) appropriate for DLBCL treatment.

  • a. Participants whose prior therapy includes chimeric antigen receptor T-cell (CAR-T-cell) therapy are eligible.
  • b. Participants who underwent stem cell transplant (SCT) > 100 days for autologous SCT or > 180 days for allogeneic SCT before study drug administration.
  • c. Participants who have been ineligible for SoC DLBCL treatments may be eligible at the investigator's discretion, upon sponsor approval.

• Participants must have at least 1 bi-dimensional tumor lesion at screening that is measurable by computerized tomography (CT) and/or magnetic resonance imaging (MRI) according to the Lugano criteria. Bi-dimensionally measurable tumor lesion by CT and/or MRI is defined as longest diameter of > 1.5 centimeters (cm) for lymph nodes and > 1.0 cm for extranodal disease.

• Participants must have life expectancy of > 3 months from the start of treatment.

• Participants must have Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.

• Participants must have met ALL the following laboratory criteria:

  • a. absolute neutrophil count (ANC) >= 1.0 × 10^9 cells per liter with no myeloid growth factors (granulocyte colony-stimulating factor [G-CSF] or granulocyte-macrophage colony-stimulating factor preparations) administered within 2 weeks of Cycle 1 Day 1.
  • b. platelet count >= 50 × 10^9 cells per liter with no Thrombopoietin-receptor agonists agents or platelet transfusions given within 2 weeks of Cycle 1 Day 1.
  • c. hemoglobin >= 8.0 grams per deciliter (g/dL) with no erythropoietin stimulating agents or peripheral red blood cell (PRBC) transfusions within 2 weeks of Cycle 1 Day 1
  • d. creatinine clearance (CLcr) to be >= 50 milliliter per minute (ml/min) either measured or estimated using the Cockcroft-Gault formula.
  • e. total bilirubin (or direct bilirubin for patients with Gilbert's disease < 1.5 × upper limit of normal (ULN)
  • f. alanine transaminase (ALT) ≤ 3.0 × ULN (or <= 5.0 x ULN if liver involvement).
  • g. aspartate aminotransferase (AST) <= 3.0 × ULN (or <= 5.0 x ULN if liver involvement).
  • h. international normalized ratio (INR) or prothrombin time (PT) <= 1.5 x ULN (unless on therapeutic anticoagulants).
  • i. Activated partial thromboplastin time <= 1.5 x ULN (unless on therapeutic anticoagulants).

• Have adequate serum albumin, as determined by: a. albumin >= 3.0 g/dL.

• QT interval correction for heart rate using Fridericia's formula (QTcF) <= 480 milliseconds determined as the average of 3 QTcF values from the triplicate electrocardiogram (ECG) obtained at screening.

• Women of reproductive potential must have a negative highly sensitive pregnancy test within 72 hours before the start of treatment. Women who are postmenopausal or permanently sterilized (eg, tubal occlusion, hysterectomy, bilateral salpingectomy) may be considered as not of reproductive potential.

• Participants of reproductive potential must agree either to abstain continuously from heterosexual intercourse or to use a highly effective birth control method from signing the informed consent until the short term follow-up (STFU) visit for females and until 90 days after the last dose of MT-3724 for males.

• Participants must be able to comply with all study-related procedures and medication use.

Exclusion Criteria

Prior or Current Therapies

• Received any amount of anti-CD20 monoclonal antibodies (mAbs) within the following periods before the start of treatment:

  • a. Rituximab (Rituxan®/MabThera® or rituximab biosimilar): within 84 days (12 weeks); if a participant has received rituximab within 37 weeks before the start of treatment, then serum rituximab level must be negative (< 500 nanograms per milliliter [ng/mL]) at screening.
  • b. Obinutuzumab (Gazyva®/Gazyvaro®): 184 days c. Ofatumumab (Arzerra®): 88 days d. Any other anti-CD20 agents (eg, investigational agents), the washout period is 5 half-lives. The investigator must contact the medical monitor to discuss the most Compound: MT-3724 appropriate washout for non-approved CD20-targeting agents, where the half-life (t1/2) is not known.

• Received approved or investigational treatment for DLBCL within 4 weeks before the start of treatment. For small molecules (MW < 0.9 kilodaltons [kDa]), the washout is 5 half-lives or at least 2 weeks. Radioimmunoconjugates are excluded within 12 weeks before the start of treatment.

• Received radiation therapy to tumor lesions that would serve as target lesions (measurable disease) within 4 weeks before the start of treatment, unless the lesion exhibited objective progression between radiation therapy and screening according to the Lugano Classification

  o a. Palliative radiation therapy to non-target lesions may be permitted at the investigator's discretion after consultation with the medical monitor and sponsor.

• Require the use of systemic immune modulators during study treatment:

  • a. Systemic immune modulators include, but are not limited to, systemic corticosteroids at doses > 20 milligrams per day (mg/day) of prednisone equivalent, cyclosporine and tacrolimus.
  • b. The use of non-steroidal anti-inflammatory drugs (NSAIDS) is permitted.

• Received any live vaccines within 4 weeks before the start of treatment.

• Prior treatment with MT-3724.

Medical History

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

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

• Known or suspected hypersensitivity to the study drug or excipients contained in the study drug formulation.

• Current evidence of hypersensitivity or other underlying illness requiring systemic corticosteroids at doses > 20 mg/day prednisone equivalent.

• Current evidence of uncontrolled human immunodeficiency syndrome (HIV), hepatitis B virus (HBV) or /hepatitis C virus (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 participants with positive viral serology:

  • a. Participants with HIV and an undetectable viral load and CD4+ T-cell (CD4+) counts >= 350 cells per milliliter may be enrolled, but must be taking appropriate opportunistic infection prophylaxis, if clinically relevant.
  • b. Participants with positive HBV serology are eligible if they have an undetectable viral load and the participant will receive antiviral prophylaxis for potential HBV reactivation per institutional guidelines.
  • c. Participants with positive HCV serology are eligible if quantitative polymerase chain reaction (PCR) for plasma HCV ribonucleic acid (RNA) is below the lower limit of detection. Concurrent antiviral HCV treatment per institutional guidelines is allowed.

• Current evidence of incomplete recovery from surgery or radiotherapy before start of treatment, or planned surgery or radiotherapy from the start of treatment until the end of treatment (EoT) visit, except minor elective surgery deemed acceptable by the investigator or palliative radiation therapy to non-target lesions.

• History of cardiovascular, renal, hepatic or any other disease within 3 months before the start of treatment that in the investigator's opinion, 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.

• 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. Participants with prior, curatively treated cancer > 2 years ago before the start of treatment can be enrolled.

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

  • a. Had radiotherapy or another appropriate therapy for the brain or spinal metastases; concurrent prophylactic treatment is allowed
  • b. Neurologic symptoms must be stable and no worse than Grade 2
  • c. Have evidence of stable brain or spinal disease on CT or MRI scan obtained within 4 weeks before signing the informed consent and compared with prior imaging results
  • d. Do not require steroid therapy (or, if applicable, have been stable on dose of no more than prednisone 20 mg/day or equivalent by C1D1)

• Women who are pregnant or breastfeeding.

• History of non-adherence to the schedule of procedures or medication use. 18. Current evidence of Graft vs Host Disease

• History or current evidence of significant cardiovascular disease including, but not limited to, the following conditions:

  • a. Unstable angina (symptoms of angina at rest) or new-onset angina within 3 months before the start of treatment.
  • b. Arterial thrombosis or pulmonary embolism within 3 months before the start of treatment.
  • c. Myocardial infarction or stroke within 3 months before the start of treatment.
  • d. Pericarditis (any CTCAE grade), pericardial effusion (CTCAE Grade >= 2), non-malignant pleural effusion (CTCAE Grade ≥ 2) or malignant pleural effusion (CTCAE Grade >= 3) within 3 months before the start of treatment with MT-3724.
  • e. Congestive heart failure (New York Heart Association [NYHA] Class III or IV) at screening or left ventricular ejection fraction (LVEF) <= 45 percent (%), assessed by echocardiogram (ECHO) or multigated acquisition (MUGA) scan within 1 month before starting study treatment (inclusion of participants with LVEF between 40% to 45% should be discussed with the medical monitor and approved by the sponsor). (ECHO or MUGA performed within 6 months before screening and at least 28 days after the last cancer therapy is acceptable provided the participant has not received any potentially cardiotoxic agents since then).
  • f. Cardiac arrhythmia requiring anti-arrhythmic therapy at screening. Participants receiving digoxin, calcium channel blockers, or beta-adrenergic blockers are eligible at the investigator's discretion after consultation with medical monitor and sponsor if the dose has been stable for >= 2 weeks before the start of treatment with MT-3724. Participants with sinus arrhythmia and infrequent premature ventricular contractions are eligible at the investigator's discretion.