MT-3724NHL001: Safety, PD & Efficacy of MT-3724 for the Treatment of Patients With Relapsed or Refractory DLBCL

Sponsor

Molecular Templates, Inc. (Industry)

Overall Status

Terminated

CT.gov ID

NCT02361346

Collaborator

(none)

130

Enrollment

Locations

Arms

73.6

Duration (Months)

3.2

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Non-Hodgkin's B-cell Lymphoma Leukemia, Lymphocytic, Chronic, B-Cell Small Lymphocytic Leukemia Diffuse Large B Cell Lymphoma Blood Cancer Hematological Malignancy	Drug: MT-3724 Phase 1 Drug: MT-3724 Phase 2	Phase 1/Phase 2

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

130 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Feb 1, 2015

Actual Primary Completion Date :

Mar 22, 2021

Actual Study Completion Date :

Mar 22, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: MT-3724 Phase 1 5 mcg/kg/dose Phase 1: MT-3724 5 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 Intravenous dosing M-W-F X 2 weeks; 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.
Experimental: MT-3724 Phase 1 10 mcg/kg/dose Phase 1: MT-3724 10 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 Intravenous dosing M-W-F X 2 weeks; 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.
Experimental: MT-3724 Phase 1 20 mcg/kg/dose Phase 1: MT-3724 20 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 Intravenous dosing M-W-F X 2 weeks; 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.
Experimental: MT-3724 Phase 1 50 mcg/kg/dose Phase 1: MT-3724 50 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 Intravenous dosing M-W-F X 2 weeks; 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.
Experimental: MT-3724 Phase 1 100 mcg/kg/dose Phase 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 Intravenous dosing M-W-F X 2 weeks; 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.
Experimental: MT-3724 Phase 1 75 mcg/kg/dose Phase 1b: MT-3724 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 Phase 1 portion of the study)	Drug: MT-3724 Phase 1 Intravenous dosing M-W-F X 2 weeks; 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.
Experimental: MT-3724 Phase 1b 50 mcg/kg/dose Phase 1b: MT-3724 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	Drug: MT-3724 Phase 1 Intravenous dosing M-W-F X 2 weeks; 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.
Experimental: MT-3724 Phase 2 50 mcg/kg/dose Phase 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 2 Intravenous dosing on M-W-F x 2 weeks; 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.

Outcome Measures

Primary Outcome Measures

Tolerability as measured by number of subjects with dose limiting toxicities [28 days (Part 1), 21 Days (Part 2 and Part 3)]
Evaluation of tolerability of MT-3724 measured by number of subjects with dose limiting toxicities (DLTs)
Safety as measured by number of subjects with Adverse Events using CTCAE [28 days (Part 1); 21 days (Part 2)]
Safety measured by number of subjects with Adverse Events using CTCAE Version 4.03 (Part 1 and 2)
Efficacy of MT-3724 (Part 3) [Time Frame: up to 47 weeks (baseline, every 6 weeks during treatment and at the end of treatment visit, which should occur 10-14 days after the last dose)]
Determine the efficacy of MT-3724 based on the overall response rate (ORR) by the revised Lugano Classification for Lymphoma adjusted according to LYRIC (lymphoma response to immunomodulatory therapy criteria) (Cheson et al, 2014, 2016). Overall response rate is defined as the proportion of subjects with either a CR or a PR as determined by independent, blinded central review.

Secondary Outcome Measures

PK Assessment of MT-3724 by Cmax [Days 1, 5, 8, 12, 23 and 28 (Part 1, 1 cycle-28 days; and Part 2, 21-day cycles); Day 1 and Day 12 of Cycle 1 (each day is 21 cycles) (Part 3)]]
Cmax is the maximum observed serum concentration of free MT-3724 include
PK Assessment of MT-3724 by tmax [Days 1, 5, 8, 12, 23 and 28 (Part 1, 1 cycle-28 days; and Part 2, 21-day cycles); Day 1 and Day 12 of Cycle 1 (each day is 21 cycles) (Part 3)]]
tmax is the time to maximum observed serum concentration of free MT-3724
PK Assessment of MT-3724 by AUC0-4 [Days 1, 5, 8, 12, 23 and 28 (Part 1, 1 cycle-28 days; and Part 2, 21-day cycles); Day 1 and Day 12 of Cycle 1 (each day is 21 cycles) (Part 3)]]
AUC0-4 is area under the concentration versus time curve (AUC) from time zero to 4 hours after the end of infusion
PK Assessment of MT-3724 by AUC0-inf [Days 1, 5, 8, 12, 23 and 28 (Part 1, 1 cycle-28 days; and Part 2, 21-day cycles); Day 1 and Day 12 of Cycle 1 (each day is 21 cycles) (Part 3)]]
AUC0-inf is area under the concentration versus time curve (AUC) from time zero extrapolated to infinity
PK Assessment of MT-3724 by AUClast [Days 1, 5, 8, 12, 23 and 28 (Part 1, 1 cycle-28 days; and Part 2, 21-day cycles); Day 1 and Day 12 of Cycle 1 (each day is 21 cycles) (Part 3)]]
AUClast is area under the concentration versus time curve (AUC) from time zero to the last sampling time point within the dosing interval
PK Assessment of MT-3724 by t1/2 [Days 1, 5, 8, 12, 23 and 28 (Part 1, 1 cycle-28 days; and Part 2, 21-day cycles); Day 1 and Day 12 of Cycle 1 (each day is 21 cycles) (Part 3)]]
t1/2 is elimination half-life
PK Assessment of MT-3724 by Vz [Days 1, 5, 8, 12, 23 and 28 (Part 1, 1 cycle-28 days; and Part 2, 21-day cycles); Day 1 and Day 12 of Cycle 1 (each day is 21 cycles) (Part 3)]]
Vz is a volume of distribution
PK Assessment of MT-3724 by CL [Days 1, 5, 8, 12, 23 and 28 (Part 1, 1 cycle-28 days; and Part 2, 21-day cycles); Day 1 and Day 12 of Cycle 1 (each day is 21 cycles) (Part 3)]]
CL is clearance
PD as measured by clinical symptoms, immunogenicity [Days 1, 5, 8, 12, 23 and 28 (Part 1, 1 cycle-28 days; and Part 2, 21-day cycles); Day 1 and Day 12 of Cycle 1 (each day is 21 cycles) (Part 3)]Days 1, 5, 8, 12, 23, and 28 (Part 1 and 2); Day 1, Day 12 of Cycle 1 (Part 3)]
Evaluation of the pharmacodynamic profile of MT-3724
Efficacy of MT-3724 (Part 3) as based on ORR [up to 47 weeks (baseline, every 6 weeks during treatment and at the end of treatment visit, which should occur 10-14 days after the last dose)]
ORR defined as the proportion of subjects with either a CR or a PR as determined by investigator assessment determined by investigator assessment
Efficacy of MT-3724 (Part 3) as based on DOR [up to 47 weeks (baseline, every 6 weeks during treatment and at the end of treatment visit, which should occur 10-14 days after the last dose)]
Time from initial documentation of tumor response (PR or CR) to disease progression.
Efficacy of MT-3724 (Part 3) as based on DCR [up to 47 weeks (baseline, every 6 weeks during treatment and at the end of treatment visit, which should occur 10-14 days after the last dose)]
Description: Percentage of subjects who have achieved CR, PR and SD (defined as SD for 3 months or longer).
Efficacy of MT-3724 (Part 3)as based on PFS [up to 47 weeks (baseline, every 6 weeks during treatment and at the end of treatment visit, which should occur 10-14 days after the last dose)]
PFS is defined as the time from study enrollment to the earliest date of disease progression or death from any cause.
Efficacy of MT-3724 (Part 3) as based on OS [up to 47 weeks (baseline, every 6 weeks during treatment and at the end of treatment visit, which should occur 10-14 days after the last dose)]
Overall survival is defined as the time from study enrollment to death from any cause
PD as measured by B-cell count and immunophenotype in peripheral blood as determined by flow cytometry measured against MT-3724 serum concentrations at pre-specified time points [up to 47 weeks (screening, day 1 of cycle 1, day 12 of cycle 1 (cycle is 21 days), and end of treatment, which should occur 10-14 days after the last dose)]
Evaluation of the pharmacodynamic profile of MT-3724
Immunogenicity as measured by MT-3724 anti-drug antibody (ADA) titer [up to 47 weeks (screening, day 1 of cycle 1, day 12 of cycle 1 (cycle is 21 days), and end of treatment, which should occur 10-14 days after the last dose)]
Evaluation of the Immunogenicity profile of MT-3724
Quality of life as assessed through Euro-QoL Questionnaire (Part 3) [up to 50 weeks (screening, day 1 of every other cycle (each cycle is 21 days), at end of treatment (which is 10-14 days after the last dose), and short-term follow-up visit (which is up to 33 days after the last dose)]
The Euro-Quality-of-Life-5 -dimension questionnaire assesses five states (mobility, self care, usual activities, pain / discomfort, and anxiety / depression) at five different levels - no problems, slight problems, moderate problems, severe problems, and extreme problems.
Safety as measured by number of subjects with Adverse Events using CTCAE [21 days]
Safety measured by number of subjects with Adverse Events using CTCAE v 5.0 (Part 3)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Men or women, age 18 years or older

Part 1:

• Histology based upon bone marrow biopsies and/or fine needle aspirates as the sole means of diagnosis are not acceptable. All subtypes of B-cell NHL may be considered for the MT-3724 dose escalation. Presence of lymphadenopathy and/or splenomegaly with histopathological evaluation of a lymph node biopsy consistent with CLL.

Part 2:

Diffuse large B cell lymphoma (DLBCL). Histology based upon bone marrow biopsies and/or fine needle aspirates as the sole means of diagnosis are not acceptable.
Subjects must have received at least one anti-CD20 antibody containing regimen that resulted in initial measurable response (partial or complete remission), followed by relapse/ recurrence.
Life expectancy > 3 months.
Eastern Cooperative Oncology Group (ECOG) performance score of ≤2.
All lymphoma subjects are required to have measurable disease
Patients must be at least 28 days past their last course of lymphoma
Received any amount of anti-CD20 MAb therapy within the following periods before the start of treatment
Received any amount of anti-CD20 MAb within the following periods before the start of treatment:
Rituximab (Rituxan®): if a subject had received any amount of rituximab within 365 days of planned dose day 1 then a serum rituximab level must be negative (<500 ng/ml) at the screening period
Obinutuzumab (Gazyva®): 184 days
Ofatumumab (Arzerra®): 88 days
ibritumomab tiuxetan (Zevalin®): 10 days
Adequate kidney function, assessed by the estimated glomerular filtration rate (eGFR) ≥60 mL/min
Female patients of childbearing potential must have a negative serum or urine pregnancy test within 3 days prior to initiating dosing. Male and female subjects with reproductive potential must agree to use acceptable contraceptive methods until the end of study visit.
Patients with known central nervous system metastases may be enrolled if they have received radiotherapy, do not require chronic steroid therapy, have had computed tomography or magnetic resonance imaging of the brain within 1 month of study entry that shows stable disease and they have no neurological symptoms other than low grade neuropathy.

Exclusion Criteria:

History of another cancer other than basal cell carcinoma or cervical intraepithelial neoplasia (CIN; i.e., cervical cancer in situ).
Potential subjects cannot have experienced a significant (CTCAE Grade 3 or 4 with or without neutropenia) infection within 2 weeks of the first dose of MT-3724.
Ongoing use of any approved or investigational antineoplastic therapies
Systemic corticosteroid therapy at a prednisone dose > 20mg/day (or equivalent) within 14 days prior to study enrollment
Potential subjects with pre-existing AEs at screening that are severe or life threatening by CTCAE, v. 4.03 should not be enrolled.
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.
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.
Potential subjects must not have received any vaccines for 28 days prior to administration of their first dose of MT-3724 and should not receive any vaccine during the study or within 28 days after their last dose of MT-3724. The single exception to this exclusion is for the annual influenza (flu) vaccine which can be given up to 14 days prior to first dose.
History of hypersensitivity to study drug or to compounds of a similar class, or whose past history suggests an increased potential for an adverse hypersensitivity reaction to MT-3724 should not be enrolled.
Patients with known active Hepatitis A or C, HIV or a present history of Hepatitis B
Potential subjects who have undergone allogeneic hematopoietic stem cell transplantation.
Women who are pregnant or breastfeeding.
Potential subjects who have had major surgery within 6 weeks prior to the first dose of study drug or have major surgery planned during the first 12 weeks post MT 3724 exposure.

Part 3

Inclusion Criteria:

Subjects must have relapsed or refractory diffuse large B-cell lymphoma (DLBCL) according to the Revised European American Lymphoma/World Health Organization (REAL/WHO) classification.
Subjects must have received at least 2 standard of care regimens for NHL treatment.
Subjects must have at least one tumor lesion at screening
Subjects must have life expectancy of >3 months from the start of treatment.
Subjects must have ECOG performance status of 0-2.
Adequate kidney function
QTcF (Fridericia) ≤480 ms determined as the average of three QTcF values from the triplicate ECG obtained at screening.
LVEF ≥45% by MUGA or echocardiogram obtained at screening.
Female patients of childbearing potential must not be pregnant.. Male and female subjects with reproductive potential must agree to use acceptable contraceptive methods until the end of study visit.
Subject must be able to comply with all study-related procedures and medication use.

Exclusion Criteria:

Received any amount of anti-CD20 MAb within the following periods before the start of treatment:
Rituximab (Rituxan®/MabThera® or rituximab biosimilar): if administered within 12 to 37 weeks before the start of treatment, then serum rituximab level must be assessed during the screening and confirmed as negative (<500 ng/mL)
Obinutuzumab (Gazyva®/Gazyvaro®): 184 days.
Ofatumumab (Arzerra®): 88 days.
Received approved or investigational treatment for NHL (except anti-CD20 MAb and radioimmunoconjugates) within 4 weeks before the start of treatment. Radioimmunoconjugates are excluded within 12 weeks before the start of treatment.
Received radiation therapy to target lesions ) within 4 weeks before the start of treatment, unless the lesions exhibited objective progression between radiation therapy and screening

Palliative radiation therapy to non-target lesions within 4 weeks before the start of treatment may be permitted at the investigator's discretion.

Received systemic immunosuppressive agents (except prescribed corticosteroids at doses ≤20 mg/day prednisone equivalent) within 2 weeks before the start of treatment
Received any vaccines except injectable flu (inactivated or recombinant) vaccine within 4 weeks before the start of treatment, or likely to require any vaccines except injectable flu vaccine at any time from the start of treatment until 28 days after the last dose of MT-3724.
Received allogeneic stem cell transplant.
Current evidence of CTCAE Grade ≥2 (significant) 1 toxicity before the start of treatment, except for hair loss and those significant toxicities permitted in other eligibility criteria. Subjects with significant permitted in other eligibility criteria. Subjects with significant
History or current evidence of significant infection, systemic infection or wound within 2 weeks before the start of treatment.

Subjects with significant infection that has stabilized or improved with oral antibiotics before the start of treatment may be eligible at the investigator'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
Patients with known active Hepatitis C, HIV or a present history of Hepatitis B
Current evidence of incomplete recovery from surgery or radiotherapy at screening, or planned surgery or radiotherapy from the start of treatment until the short term follow-up visit, except minor elective surgery or palliative radiation therapy to non-target lesions deemed acceptable by the investigator.
History of cardiovascular, renal, hepatic or any other disease within ≤3 months before the start of treatment
History of another primary malignancy within the past 3 years (except for ductal breast cancer in situ, non-melanoma skin cancer, prostate cancer not requiring treatment, and cervical carcinoma in situ) that required systemic drug therapy or radiotherapy.
Current evidence of new or growing brain or spinal metastases during screening.
Women who are pregnant or breastfeeding.
History of non-adherence to the schedule of procedures or medication use

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Arizona	Tucson	Arizona	United States	85724
2	Innovative Clinical Research Institute, LLC	Whittier	California	United States	90602
3	21st Century Oncology - Jacksonville	Jacksonville	Florida	United States	32204
4	Orlando Health, Inc.	Orlando	Florida	United States	32806
5	Orlando Health, Inc.	Orlando	Florida	United States
6	BRCR Medical Center	Plantation	Florida	United States	33322
7	ASCLEPES Research Centers	Weeki Wachee	Florida	United States	34607
8	Columbus Regional Research Institute	Columbus	Georgia	United States	31904
9	University of Illinois, Cancer Center	Chicago	Illinois	United States	60612
10	Healthcare Research Network III, LLC	Tinley Park	Illinois	United States
11	Carle Foundation Hospital	Urbana	Illinois	United States
12	Norton Healthcare, Inc	Louisville	Kentucky	United States
13	New York University Langone Medical Center	New York	New York	United States	10016
14	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10065
15	University of North Carolina	Chapel Hill	North Carolina	United States	27599
16	MD Anderson Cancer Center	Houston	Texas	United States	77030
17	UT Health San Antonio Cancer	San Antonio	Texas	United States	78229
18	Grodno University Hospital	Grodno		Belarus
19	Minsk City Clinical Oncology Center	Minsk		Belarus	220013
20	Cross Cancer Institute	Edmonton	Alberta	Canada
21	Cancer Centre of Southeastern Ontario at Kingston General Hospital	Kingston	Ontario	Canada	K7L 2V7
22	Princess Margaret Cancer Centre	Toronto	Ontario	Canada	M5G 2M9
23	Montreal Oncology Research	Quebec		Canada	H1M 1B1
24	LLC ARENSIA Exploratory Medicine	Tbilisi		Georgia	0112
25	Rabin Medical Center, Davidoff Cancer Center, Hemato-Oncology Institute	Petah-Tikva		Israel	49100
26	Chaim Sheba Medical Center, Department of Hematology	Ramat Gan		Israel
27	The Tel Aviv Sourasky Medical Center, Department of Hematology and Bone Marrow Transplantation	Tel-Aviv		Israel
28	ARENSIA Exploratory Medicine,	Chisinau		Moldova, Republic of	MD-2025
29	Maria Sklodowska-Curie National Institute of Oncology - National Research Institute	Gliwice		Poland
30	University Hospital in Krakow, Teaching Unit of the Hematology Department	Kraków		Poland
31	Frederic Chopin Provincial Teaching Hospital, Teaching Department of Hematology	Rzeszów		Poland	35-055
32	Our Doctor Clinical Trials Center	Torun		Poland
33	Institute of Hematology and Transfusion Medicine, Department of Hematology	Warsaw		Poland
34	Jan Mikulicz Radecki University Hospital in Wroclaw, Department and Clinic of Hematology, Blood Neoplasms and Bone Marrow Transplantation	Wroclaw		Poland	50-367
35	Clinical Center Kragujevac, Clinic of Hematology	Kragujevac		Serbia
36	Clinical Center of Vojvodina, Clinic of Hematology	Novi Sad		Serbia
37	Catalan Institute of Oncology (ICO) - Hospital Duran i Reynals, Department of Clinical Hematology	Barcelona		Spain
38	University Hospital Vall d'Hebron (HUVH), Department of Hematology	Barcelona		Spain
39	Hospital Universitario QuironSalud Madrid	Madrid		Spain	28223
40	University Hospital Virgen del Rocio (HUVR), Department of Hematology	Seville		Spain
41	Medical Center of Limited Liability Company "Medical Centre Named by Academician Yurii Spizhenko	Kyiv		Ukraine	08112