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

NCT02361346 | Terminated Phase 1 Results DMC

• 1 other identifier: MT-3724_NHL_001
• Study Type: interventional
• Target: 38
• Locations: 10 countries
• Sites: 41

Brief Summary

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.

Conditions

Non-Hodgkin's B-cell Lymphoma; Leukemia, Lymphocytic, Chronic, B-Cell; Small Lymphocytic Leukemia; Diffuse Large B Cell Lymphoma; Blood Cancer; Hematological Malignancy

Keywords

CD20; immunotoxin; NHL; non-Hodgkin's lymphoma; lymphoma; cancer; antibodies; immunotherapy; safety; pharmacokinetics; maximum tolerated dose; MT-3724; relapsed; refractory; leukemia; CLL; SLL; DLBCL; efficacy

Outcome Measures

Primary Outcomes (15)

• Part 1: Number of Participants With Dose Limiting Toxicities of a Single Cycle of MT-3724

  The MTD is defined to be the dose cohort below which participants experience dose-limiting toxicities during cycle 1. Dose-limiting toxicities were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0

  Days 1, 3, 5, 8, 10 and 12

• Part 1 and 2: Maximum Observed Concentrations (Cmax) of MT-3274

  Blood samples were collected at indicated timepoints for the determination of Cmax of MT-3274.

  Part 1 and 2 : Days 1, 3 and 12

• Part 1 and 2: Time to Achieve Cmax (Tmax) of MT-3724

  Blood samples were collected at indicated timepoints for the determination of tmax.

  Part 1 and 2: Days 1, 3 and 12

• Part 1 and 2: Area Under the Plasma Concentration Time Curve From 0 to 4 Hours (AUC [0-4]), AUC (0-infinity) and AUC From Dosing to Last Measurable Concentration (AUClast) of MT-3724

  Blood samples were collected at indicated timepoints for the determination of AUC (0-4), AUC (0-infinity) and AUClast.

  Part 1 and 2: Days 1, 3 and 12

• Part 1 and 2: Half Life (t1/2) of MT-3724

  Blood samples were collected at indicated timepoints for the analysis of t1/2 of MT-3724.

  Part 1 and 2: Days 1, 3 and 12

• Part 1 and 2: Volume of Distribution (Vz) of MT-3724

  Blood samples were collected at indicated timepoints for the analysis of Vz of MT-3724.

  Part 1 and 2: Days 1, 3 and 12

• Part 1 and 2: Clearance (CL) of MT-3724

  Blood samples were collected at indicated timepoints for the analysis of CL of MT-3724.

  Part 1 and 2: Days 1, 3 and 12

• Part 1 and 2: Absolute Values of Cluster of Differentiation 19 Plus (CD19+) for B-cell Lymphocytes

  CD19+ cells in the peripheral blood were counted as measures of malignant B-cells and were measured by flow cytometry. Flow cytometry is a technique for counting and examining microscopic particles with an electronic detection apparatus

  Part 1 and 2: Cycle 1: Days 8 and 23; Cycle 3: Day1; Cycle 5: Day 1 and Day 120 (end of study)

• Part 1 and 2: Number of Participants With Positive Anti-drug Antibody (ADA) Confirmed

  Blood samples were collected to analyze the presence of ADA that bind MT-3724. Number of participants with positive ADA confirmed has been presented.

  Part 1 and 2: Cycle 1, Day 23; Cycle 2, Day 1; Cycle 3, Day 1; Cycle 4, Day 1; Cycle 5, Day 1 and Day 120 (end of study)

• Part 3: Number of Participants Reporting Serious Treatment-emergent Adverse Events (TEAEs) and Non-serious TEAEs

  An adverse event is any untoward medical occurrence or clinical investigation in a participant administered a pharmaceutical product(s) and which does not necessarily have to have a causal relationship with this experimental treatment(s). SAE is any untoward medical occurrence, at any dose; is fatal or life-threatening, is life-threatening, results in permanently disabling; results in unplanned in-patient hospitalization or prolongation of existing hospitalization; results in a congenital abnormality or birth defect; important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when based upon appropriate medical judgment, they may jeopardize the participant or may require medical or surgical intervention.

  Up to Day 45

• Part 3: Number of Participants With Clinically Significant Laboratory Parameters

  Blood samples were collected at indicated timepoints for the analysis of laboratory parameters.

  Up to Day 45

• Part 3: Number of Participants With Clinically Significant Electrocardiogram (ECG) Values

  Standard resting 12-lead ECG assessments was performed after the participant has rested quietly for at least 5 minutes in supine or semi-recumbent position.

  Up to Day 26

• Part 3: Number Participants With Clinically Significant Vital Signs

  Vital signs including systolic and diastolic blood pressure, respiratory rate, heart rate and body temperature were assessed at indicated time points.

  Up to Day 45

• Part 3: Number of Participants With Clinically Significant Physical Findings

  Physical examination was performed by a physician or a qualified delegate at the investigating site.

  Up to Day 26

• Part 4: Overall Response Rate (ORR) in MT-3724 Treated Participants With Relapsed or Refractory DLBCL

  Overall response rate is defined as the percentage of participants with either a CR or a PR as determined by independent, blinded central review.

  Up to Day 45

Secondary Outcomes (36)

• Part 1 and 2: Number of Participants Reporting Worst Case Serious Treatment Emergent Adverse Events (TEAEs) and Non-serious TEAEs

  Up to Day 45

• Part 3: ORR in MT-3724 Treated Participants With Relapsed or Refractory DLBCL by the Lugano Classification for Lymphoma

  Up to Day 45

• Part 3: ORR in MT-3724 Treated Participants With Relapsed or Refractory DLBCL

  Up to Day 45

• Part 3: Duration of Tumor Response (DOR) in MT-3724 Treated Participants With Relapsed or Refractory DLBCL

  Up to Day 45

• Part 3: Disease Control Rate (DCR) in MT-3724 Treated Participants With Relapsed or Refractory DLBCL

  Up to Day 45

Study Arms (9)

Part 1: Cohort 1 - 5 Micrograms/Kilogram/Dose (mcg/kg/Dose)

EXPERIMENTAL

Part 1: MT-3724 5 mcg/kg/dose IV for 6 doses over 12 days, followed by dose escalations (Part 1) until recommended phase 2 dose of MT-3724 is determined

Drug: MT-3724 Phase 1

Part 1: Cohort 2- 10 mcg/kg/Dose

EXPERIMENTAL

Part 1: MT-3724 10 mcg/kg/dose IV for 6 doses over 12 days, followed by dose escalations (Part) until recommended phase 2 dose of MT-3724 is determined

Drug: MT-3724 Phase 1

Part 1: Cohort 3- 20 mcg/kg/Dose

EXPERIMENTAL

Part 1: MT-3724 20 mcg/kg/dose IV for 6 doses over 12 days, followed by dose escalations (Part 1) until recommended phase 2 dose of MT-3724 is determined

Drug: MT-3724 Phase 1

Part 1: Cohort 4- 50 mcg/kg/Dose

EXPERIMENTAL

Part 1: MT-3724 50 mcg/kg/dose IV for 6 doses over 12 days, followed by dose escalations (Part 1) until recommended phase 2 dose of MT-3724 is determined

Drug: MT-3724 Phase 1

Part 1: Cohort 5- 100 mcg/kg/Dose

EXPERIMENTAL

Part 1: MT-3724 100 mcg/kg/dose IV for 6 doses over 12 days, followed by dose escalations (Phase 1) until recommended phase 2 dose of MT-3724 is determined

Drug: MT-3724 Phase 1

Part 1: Cohort 6- 75 mcg/kg/Dose

EXPERIMENTAL

Part 1b: MT-3724 75 mcg/kg/dose IV for 6 doses over 12 days of 21-Day cycle for up to 4 additional cycles to explore safety, tolerability and tumor response to repeat doses of MT-3724 (subject will continue with dose that was tolerated in the Part 1 portion of the study)

Drug: MT-3724 Phase 1

Part 2: Cohort 7- MTD Expansion Cohort

EXPERIMENTAL

Part 2: MT-3724 IV for 6 doses administered within 14 days of 21-Day cycle up to 6 Cycles. If the Subject exhibits stable disease or PR after end of Cycle 6 and investigator determines ratio is favorable, treatment with MT- 3724 may be continued for up to additional 6 cycles.

Drug: MT-3724 Phase 1; Drug: MT-3724 Phase 2

Part 3: All MT-3724 Treated Participants

EXPERIMENTAL

Part 3: MT-3724 IV 50 µg/kg/dose administered on Days 1, 3, 5, 8, 10, and 12 of each 21-day cycle. Treatment will continue until death, disease progression, unacceptable toxicity, withdrawal of consent, or another reason for withdrawal, or until study discontinuation

Drug: MT-3724 Phase 2

Part 4: All MT-3724 Treated Participants

EXPERIMENTAL

Part 4: In this arm, subjects were planned to receive all doses of MT-3724 as IV infusion as confirmed in Part 3.

Drug: MT-3724 Phase 2

Interventions

MT-3724 Phase 1 DRUG

Intravenous dosing Days 1, 3, 5, 8, 10 and 12; MT-3724 infusion over 2 hours on each dosing day over 28 day initial cycle and then 21 week repeat cycles for up to 5 total cycles.

Part 1: Cohort 1 - 5 Micrograms/Kilogram/Dose (mcg/kg/Dose); Part 1: Cohort 2- 10 mcg/kg/Dose; Part 1: Cohort 3- 20 mcg/kg/Dose; Part 1: Cohort 4- 50 mcg/kg/Dose; Part 1: Cohort 5- 100 mcg/kg/Dose; Part 1: Cohort 6- 75 mcg/kg/Dose; Part 2: Cohort 7- MTD Expansion Cohort

MT-3724 Phase 2 DRUG

Intravenous dosing on Days 1, 3, 5, 8, 10 and 12; MT-3724 infusion over 1 hour on each dosing day over 21 day cycle up to 6 cycles and then can be continued for 6 additional cycles.

Part 2: Cohort 7- MTD Expansion Cohort; Part 3: All MT-3724 Treated Participants; Part 4: All MT-3724 Treated Participants

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Molecular Templates, Inc.: lead

Study Sites (41)

University of Arizona

Tucson, Arizona, 85724, United States

Location

Innovative Clinical Research Institute, LLC

Whittier, California, 90602, United States

Location

21st Century Oncology - Jacksonville

Jacksonville, Florida, 32204, United States

Location

Orlando Health, Inc.

Orlando, Florida, 32806, United States

Location

Orlando Health, Inc.

Orlando, Florida, United States

Location

BRCR Medical Center

Plantation, Florida, 33322, United States

Location

ASCLEPES Research Centers

Weeki Wachee, Florida, 34607, United States

Location

Columbus Regional Research Institute

Columbus, Georgia, 31904, United States

Location

University of Illinois, Cancer Center

Chicago, Illinois, 60612, United States

Location

Healthcare Research Network III, LLC

Tinley Park, Illinois, United States

Location

Carle Foundation Hospital

Urbana, Illinois, United States

Location

Norton Healthcare, Inc

Louisville, Kentucky, United States

Location

New York University Langone Medical Center

New York, New York, 10016, United States

Location

Memorial Sloan-Kettering Cancer Center

New York, New York, 10065, United States

Location

University of North Carolina

Chapel Hill, North Carolina, 27599, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

UT Health San Antonio Cancer

San Antonio, Texas, 78229, United States

Location

Grodno University Hospital

Grodno, Belarus

Location

Minsk City Clinical Oncology Center

Minsk, 220013, Belarus

Location

Cross Cancer Institute

Edmonton, Alberta, Canada

Location

Cancer Centre of Southeastern Ontario at Kingston General Hospital

Kingston, Ontario, K7L 2V7, Canada

Location

Princess Margaret Cancer Centre

Toronto, Ontario, M5G 2M9, Canada

Location

Montreal Oncology Research

Québec, H1M 1B1, Canada

Location

LLC ARENSIA Exploratory Medicine

Tbilisi, 0112, Georgia

Location

Rabin Medical Center, Davidoff Cancer Center, Hemato-Oncology Institute

Petah Tikva, 49100, Israel

Location

Chaim Sheba Medical Center, Department of Hematology

Ramat Gan, Israel

Location

The Tel Aviv Sourasky Medical Center, Department of Hematology and Bone Marrow Transplantation

Tel Aviv, Israel

Location

ARENSIA Exploratory Medicine,

Chisinau, MD-2025, Moldova

Location

Maria Sklodowska-Curie National Institute of Oncology - National Research Institute

Gliwice, Poland

Location

University Hospital in Krakow, Teaching Unit of the Hematology Department

Krakow, Poland

Location

Frederic Chopin Provincial Teaching Hospital, Teaching Department of Hematology

Rzeszów, 35-055, Poland

Location

Our Doctor Clinical Trials Center

Torun, Poland

Location

Institute of Hematology and Transfusion Medicine, Department of Hematology

Warsaw, Poland

Location

Jan Mikulicz Radecki University Hospital in Wroclaw, Department and Clinic of Hematology, Blood Neoplasms and Bone Marrow Transplantation

Wroclaw, 50-367, Poland

Location

Clinical Center Kragujevac, Clinic of Hematology

Kragujevac, Serbia

Location

Clinical Center of Vojvodina, Clinic of Hematology

Novi Sad, Serbia

Location

Catalan Institute of Oncology (ICO) - Hospital Duran i Reynals, Department of Clinical Hematology

Barcelona, Spain

Location

University Hospital Vall d'Hebron (HUVH), Department of Hematology

Barcelona, Spain

Location

Hospital Universitario QuironSalud Madrid

Madrid, 28223, Spain

Location

University Hospital Virgen del Rocio (HUVR), Department of Hematology

Seville, Spain

Location

Medical Center of Limited Liability Company "Medical Centre Named by Academician Yurii Spizhenko

Kyiv, 08112, Ukraine

Location

MeSH Terms

Conditions

Lymphoma, B-Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Large B-Cell, Diffuse; Hematologic Neoplasms; Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms; Recurrence; Leukemia

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, B-Cell; Leukemia, Lymphoid; Hematologic Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Neoplasms by Site

Results Point of Contact

• Title: Study Director
• Organization: Molecular Templates, Inc.

trials@mtem.com

512 930-0304

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 3, 2015
• First Posted: February 11, 2015
• Study Start: February 1, 2015
• Primary Completion: March 22, 2021
• Study Completion: March 22, 2021
• Last Updated: August 18, 2022
• Results First Posted: August 18, 2022

Record last verified: 2022-07

Data Sharing

• IPD Sharing: Will not share

Locations

UA (1); SE (2); MO (1); GE (1); IL (3); US (17); ES (4); PL (6); CA (4); BE (2)