Non Hodgkin Lymphoma Clinical Trial

A Study of MT-0169 in Participants With Relapsed or Refractory Multiple Myeloma or Non-Hodgkin Lymphoma

Summary

This will be a Phase 1 Open-Label, dose escalation and expansion study of MT-0169 (an Engineered toxin body (ETB) in patients with relapsed or refractory multiple myeloma or non-Hodgkin lymphoma. MT-0169 is an investigational drug that recognizes and binds to the CD38 receptor, which may be found on the surface of multiple myeloma and non-Hodgkin lymphoma cancer cells. It delivers a dose of a modified toxin that kills these cells.

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Full Description

The drug being tested in this study is called MT-0169. The study will evaluate the safety, tolerability, preliminary efficacy, PK, pharmacodynamics, and immunogenicity of MT-0169 monotherapy in participants with RRMM or RRNHL.

This study is conducted in 2 parts. The study will enroll up to 144 total participants (up to 54 participants in Part 1 and up to 90 participants in Part 2).

Part 1 (Dose Escalation): The purpose of Part 1 is to evaluate the safety and tolerability of MT-0169 in subjects with relapsed or refractory multiple myeloma (RRMM) and relapsed or refractory non-Hodgkin lymphoma (RRNHL) and to estimate the maximum tolerated dose (MTD) or the recommended Phase 2 dose (RP2D).

Part 2 (Dose Expansion): The purpose of Part 2 is to confirm the RP2D and to evaluate the preliminary clinical activity of MT-0169 monotherapy in patients with RRMM and RRNHL.

MT-0169 will be given as an intravenous (IV) infusion over 60 minutes on the same day every week (i.e., days 1, 8, 15 and 22) or every 2 weeks (i.e., days 1 and 15) of each cycle. A cycle is defined as 28 days.

In Parts 1 and 2, a subject may participate for the following three (3) periods:

Screening Period - up to 28 days before first dose of MT-0169 Treatment Period - active period where a subject will receive doses of MT-0169 over a 28-day treatment period Follow-up Period - up to 12 months after the last patient in the study to receive the last dose of MT-0169.

In both parts of the study, participants can receive MT-0169 until the cancer worsens, side effects prevent further study treatment, or until the participant leaves the study for other reasons decided by the participant, the study doctor, or the sponsor of the study. After treatment has finished, participants will have a check-up of their disease status every 12 weeks.

This multi-center trial will be conducted worldwide. The overall duration of the study will vary for each participant because they will receive study treatment until unacceptable toxicity, withdrawal of consent, death, termination of the study by the sponsor, or fulfillment of another discontinuation criterion. Participants will be followed up for 30 days after the last dose of study drug for a follow-up assessment for any side effects. Participants will then be followed every 12 weeks to check for the status of their disease up to 12 months after the last subject on the trial has the last dose of study drug, or the sponsor discontinues the study, whichever occurs first.

View Eligibility Criteria

Eligibility Criteria

Inclusion Criteria Part 1 (RRMM patients only)

Confirmed diagnosis of MM per revised IMWG diagnostic criteria
Patients with RRMM who have failed treatment with, are intolerant to, or are not candidates for available therapies that are known to confer clinical benefit

Must meet all of the following criteria for prior therapy:

Must be refractory to ≥1 proteasome inhibitor (PI), ≥1 immunomodulatory drug (IMiD), and ≥1 steroid
Must either have received ≥3 prior lines of therapy or ≥2 prior lines of therapy if 1 line included a combination of PI and IMiD (prior treatment with anti-CD38 therapy is permitted).

With measurable disease, defined as ≥1 of the following:

Serum M-protein ≥500 mg/dL (≥5 g/L) on serum protein electrophoresis (SPEP).
Urine M-protein ≥200 mg/24 h on urine protein electrophoresis (UPEP).
Serum FLC assay result with an involved FLC level ≥10 mg/dL (≥100 mg/L) if serum FLC ratio is abnormal.

Patients with serum M-protein, urine M-protein, or involved immunoglobulin FLC not meeting the measurable disease criteria above will be eligible if they have ≥1 of the following:

Bone marrow (BM) aspirate/biopsy with plasma cell percentage ≥30%
PET imaging with ≥1 plasmacytoma lesion with a single diameter of ≥2cm.
With Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1.
With normal QT interval corrected by the Fridericia method (QTcF) on screening electrocardiogram (ECG)[ QTcF of ≤450 millisecond (ms) in males or ≤470 ms in females]

Must meet the following clinical laboratory criteria at entry:

Total bilirubin ≤1.5*the upper limit of the normal range (ULN), except for Gilbert's syndrome (direct bilirubin must be <2.0*ULN)
Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≤2.5*ULN.
Estimated glomerular filtration rate (eGFR) ≥30 (mL/min/1.73 square meter [m2]), using the modification of diet in renal disease (MDRD) equation
Absolute neutrophil count (ANC) ≥1000 per cubic millimeter (/mm3) (≥1.0*109 per liter [/L]); ≥750/mm3 (≥0.75*109/L) may be acceptable for participants with >50% of plasma cells in BM
Platelet count ≥75,000/ mm3 (≥75*109/L); ≥50,000/ mm3 (≥50*109/L) may be acceptable for participants with >50% of plasma cells in BM
Hemoglobin ≥7.5 g/dL without transfusion within 7 days before the lab test.
Serum albumin ≥2.5 g/dL.

Female patients who:

are postmenopausal for at least 1 year prior to screening OR
are surgically sterile OR
If they are of childbearing potential, agree to practice 1 highly effective method of contraception and 1 additional effective barrier method at the same time from study entry through 30 days after the last dose of study drug OR
agree to practice true abstinence if in line with the preferred, usual lifestyle [periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods), withdrawal, spermicides only, and lactational amenorrhea are not acceptable. Female and male condoms should not be used together]

Male patients, even if surgically sterilized (postvasectomy) who:

Agree to practice effective barrier contraception during the entire study and through 90 days after last dose of study drug OR
Agree to practice true abstinence if in line with the preferred, usual lifestyle [periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods), withdrawal, spermicides only, and lactational amenorrhea are not acceptable. Female and male condoms should not be used together]

Inclusion criteria Part 2 (both RRMM and RRNHL patients)

ECOG performance score of 0 or 1.
Normal QTcF on screening ECG, defined as QTcF of ≤450 ms in males or ≤470 ms in females

Must meet the following clinical laboratory criteria at study entry:

Total bilirubin ≤1.5*the ULN, except for Gilbert's syndrome (direct bilirubin must be <2.0*ULN)
Serum ALT and AST ≤2.5*ULN
eGFR ≥30 mL/min/1.73 m2(MDRD equation)
ANC ≥1000 mm3 (≥1.0*109 /L); a count of ≥750/mm3 (≥0.75*109/L) may be acceptable for participant with >50% of plasma cells in BM
Platelet count ≥75,000/ mm3 (≥75*109/L); a value of ≥50,000/ mm3(≥50*109/L) may be acceptable for participants with >50% of plasma cells in BM
Hemoglobin ≥7.5 g/dL without transfusion within 7 days before the lab test
Serum albumin ≥2.5 g/dL

Female patients who:

are postmenopausal for at least 1 year prior to screening OR
are surgically sterile OR
If they are of childbearing potential, agree to practice 1 highly effective method of contraception and 1 additional effective barrier method at the same time from study entry through 30 days after last dose of study drug OR
agree to practice true abstinence if in line with the preferred, usual lifestyle [periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods), withdrawal, spermicides only, and lactational amenorrhea are not acceptable. Female and male condoms should not be used together]

Male patients, even if surgically sterilized (postvasectomy) who:

Agree to practice effective barrier contraception during the entire study and through 90 days after the last dose of study drug OR
Agree to practice true abstinence if in line with the preferred and usual lifestyle [periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods), withdrawal, spermicides only, and lactational amenorrhea are not acceptable. Female and male condoms should not be used together] Inclusion Criteria Part 2 for RRNHL patients

Pathologically confirmed diagnosis of the following NHL subtype based on local pathology report:

Mantle cell lymphoma (MCL) i. Nodal MCL
Diffuse large B-cell lymphoma (DLBCL) i. DLBCL-NOS ii. Plasmablastic lymphoma (PbL) iii. Primary effusion lymphoma (PEL). iv. Primary effusion lymphoma (PMBL)
Follicular lymphoma
Burkitt lymphoma (BL)
Peripheral T-cell lymphoma (PTCL) i. PTCL-NOS (eligible at MTD/RPTD if biopsy evidence of CD38 positivity) ii. Angioimmunoblastic T-cell lymphoma (AITL)
Extranodal NK/T-cell lymphoma (ENKTL)-nasal type
RRNHL, having failed treatment with, is intolerant to, or is determined not to be a candidate for available therapies considered standard of care (SOC) or are known to confer clinical benefit.

At least 1 measurable site of disease according to the Lugano classification for lymphoma.

A measurable nodal lesion with longest diameter (LDi) greater than 1.5cm OR
A measurable extranodal lesion with LDi greater than 1.0cm

Evidence of a CD38 positive tumor. Any of the following are acceptable:

Evidence of CD38 expression from most recent biopsy or blood sample [either flow cytometry (FCM) or immunohistochemistry (IHC)] OR
The most recently archived tissue assessed for CD38 expression by IHC OR
Fresh biopsy for CD38 expression assessment by IHC within 35 days of Cycle 1 Day 1 OR
Fresh blood sample with circulating NHL cells assessed by FCM within 35 days of Cycle 1 Day 1 (BM biopsy excisional lymph node biopsy, core biopsy of any involved organ are all acceptable methods, find needle aspirate is not. Any level of positive CD38 expression is eligible). Fine needle aspirate may be accepted on a case-by-case basis after discussion with the medical monitor of the sponsor.

Inclusion Criteria Part 2 for RRMM patients

Confirmed diagnosis of MM per IMWG diagnosis criteria:
RRMM, having failed treatment with, is intolerant to, or is determined not to be a candidate for available therapies considered SOC or are known to confer clinical benefit.

Must meet the following criteria for prior therapy:

Refractory or intolerant to ≥1 PI and ≥1 IMiD
Receipt of ≥3 prior lines of therapy or ≥2 prior lines of therapy if 1 of those lines included a combination of a PI or IMiD (prior treatment with anti-CD38 therapy is permitted except for patients enrolled in the anti-CD38 therapy naïve cohort)
Daratumumab RR cohorts: RR to daratumumab at any time during treatment. Patients RR to other anti-CD38 therapies are excluded.
Anti-CD38 therapy naïve cohort: must not have received any prior anti CD-38 therapy.

Measurable disease, defined as ≥1 of the following

Serum M-protein ≥50 mg/dL (≥5 g/L) on SPEP.
Urine M-protein ≥200 mg/24 hours on UPEP.
Serum FLC assay result with and involved FLC level ≥10 mg/dL (≥100mg/L), provided the serum FLC ratio is abnormal.

Serum M-protein, urine M-protein or involved immunoglobulin FLC not meeting measurable disease criteria if at least 1 of the following criteria is met:

BM aspirate/biopsy showing plasma cell percentage ≥30%
PET imaging showing at least 1 plasmacytoma lesion with a single diameter ≥2 cm.

Exclusion Criteria for Part 1 (RRMM patients only):

With polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes (POEMS) syndrome, monoclonal gammopathy of unknown significance, smoldering myeloma, solitary plasmacytoma, amyloidosis, Waldenström macroglobulinemia, or Immunoglobulin M (IgM) myeloma.
With sensory or motor neuropathy of NCI CTCAE V5 Grade ≥3.

Have received final dose of any of the following treatments/procedures within the following interval before the first dose of MT-0169:

Myeloma-specific therapy, including PIs and IMiDs: 14 days
Anti-CD38 (a) therapy: Isatuximab 90 days; daratumumab 60 days
Corticosteroid therapy for myeloma: 7 days
Radiation therapy for localized bone lesions: 14 days
Major surgery:30 days
Autologous stem cell transplant: 90 days
Investigational therapy: 30 days
Have received an allogeneic stem cell transplant or organ transplantation.
Have not recovered to Grade ≤1 or baseline, from adverse reactions to prior myeloma treatment or procedures (chemotherapy, immunotherapy, radiation therapy) excluding alopecia and Grade 2 neuropathy.
With clinical signs of central nervous system (CNS) involvement of MM.
With a history of myelodysplastic syndrome or another malignancy other than MM except for the following: any malignancy in complete remission for 3 years, adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, or asymptomatic prostate cancer without known metastatic disease and not requiring therapy or requiring only hormonal therapy and with normal prostate-specific antigen level for ≥1 year before the start of study therapy.
With known or suspected light chain amyloidosis of any organ (amyloid on the BM biopsy without other evidence of amyloidosis is acceptable).

With any of the following cardiovascular conditions:

Congestive heart failure (NYHA) class ≥II or left ventricular ejection fraction (LVEF <40%, cardiac myopathy, active ischemia, or any other uncontrolled cardiac condition or myocardial infarction or clinically significant arrhythmia requiring therapy including anticoagulants within the past 6 months or at screening
Resting tachycardia (heart rate of > 100 bpm) at screening
Clinically significant uncontrolled hypertension at screening
Cardiac MRI at screening demonstrates evidence of infiltrative disease of the myocardium

With a history of document significant pleural or pericardial effusions within 3 months before the start of treatment, including:

Pericarditis (any Grade)
Pericardial effusion (Grade ≥2)
Non-malignant pleural effusion (Grade ≥2)
Malignant pleural effusion (Grade ≥2)
Patients with a history of noncardiogenic pulmonary edema associated with diffuse peripheral edema and history of intravascular hypovolemia associated with systemic antineoplastic therapy.

With chronic or active infection requiring systemic therapy, history of symptomatic viral infection that has not been fully cured.

With HIV and an undetectable viral load and CD4+ T-cell (CD4+) counts ≥350 cells/mL may be allowed but patient must be taking appropriate opportunistic infection prophylaxis if clinically relevant
With positive HBV serology may be allowed if undetectable viral load, receiving antiviral prophylaxis for potential HBV reactivation per institutional guidelines
With positive HCV serology may be allowed if quantitative PCR for plasma HCV RNA is below the lower limit of detection. Concurrent antiviral HCV treatment per institutional guidelines is allowed.
Have received a live attenuated vaccine within 28 days of first dose of MT-0169.
With a history of ≥ Grade 2 systemic inflammatory response syndrome (SIRS)/ cytokine release syndrome (CRS) reactions following infusion with any monoclonal antibodies or Chimeric Antigen Receptor (CAR) T therapy
With a chronic condition requiring systemic corticosteroids at >10 mg/day of prednisone or equivalent.
Are lactating and breastfeeding or have a positive serum pregnancy test during the screening period or patients of reproductive potential who are not employing an effective birth control
With a concurrent medical or psychiatric illness that would preclude study conduct and assessment including, but not limited to, uncontrolled medical conditions, active infection, risk of bleeding, diabetes mellitus, pulmonary disease, alcoholic liver disease, or primary biliary cirrhosis.
With known allergy or intolerance to any of the drugs used in the study or excipients in MT-0169
With a history of hypersensitivity or serious toxic reaction to kanamycin or another aminoglycoside.

Exclusion Criteria for Part 2 NHL patients only:

With known CNS lymphoma (exception if history of CNS disease and evidence of SD on neuroimaging separated by at least 4 weeks and within 4 weeks of Cycle 1 Day 1)

Have received a final dose of any of the following treatments/procedures within the following minimum interval before the first dose of MT-0169:

Nitrosoureas: 6 weeks
Chemotherapy: 4 weeks
Small molecules (<0.9 kDa): 5 half-lives or at least 2 weeks
Therapeutic antibodies: 4 weeks
Radio/toxin -immunoconjugates: 12 weeks
Radiation therapy - target lesion (measurable disease): 4 weeks
Radiation therapy - nontarget lesion: 2 weeks
Investigational chemotherapeutic agents or antibodies: 4 weeks
Daratumumab: 60 days
Isatuximab: 90 days
(MCL) Bruton's tyrosine kinase inhibitors: 2 weeks or 5 half-lives, whichever is longer
Major surgery (determined by the principal investigator and Sponsor): 4 weeks
Autologous stem cell transplant: 100 days
Allogenic stem cell transplant: 180 days (patients with graft vs host disease > Grade 1 will be excluded)

With a history of myelodysplastic syndrome or malignancy (other than NHL) except for the following: any malignancy in complete remission for 3 years, adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, or asymptomatic prostate cancer without known metastatic disease and not requiring therapy or requiring only hormonal therapy and with normal prostate-specific antigen level for ≥1 year before the start of study therapy

Exclusion Criteria for Part 2 RRMM patients only:

With POEMS syndrome, monoclonal gammopathy of unknown significance, smoldering myeloma, solitary plasmacytoma, amyloidosis, Waldenström macroglobulinemia, IgM myeloma.

Have received a final dose of any of the following treatments/procedures within the following interval before the first dose of MT-0169:

Myeloma-specific therapy, including PIs and IMiDs: 14 days
Anti-CD38 therapy - Isatuximab: 90 days
Anti-CD38 therapy - Daratumumab: 60 days
Corticosteroid therapy for myeloma: 7 days
Radiation therapy for localized bone lesions: 14 days
Major surgery: 30 days
Autologous stem cell transplant: 90 days
Investigational therapy: 30 days
Have received an allogenic stem cell or organ transplant.
With clinical signs of CNS involvement of MM.
With a history of myelodysplastic syndrome or another malignancy other than MM except or any malignancy in complete remission for 3 years, adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, or asymptomatic prostate cancer without known metastatic disease and not requiring therapy or requiring only hormonal therapy and with normal prostate-specific antigen level for >1 year before the start of study therapy.

With known or suspected light chain amyloidosis of any organ (amyloid on BM biopsy without other evidence of amyloidosis is acceptable).

Exclusion Criteria for Part 2 (both RRMM and NHL patients):

Failed to recover to Grade ≤1 or baseline from adverse reactions to prior treatment or procedures (chemotherapy, immunotherapy, radiation therapy) excluding alopecia and stable Grade 2 neuropathy.

With any of the following cardiovascular conditions:

Congestive heart failure (NYHA) class ≥II LVEF <40%, cardiac myopathy, active ischemia, or any other uncontrolled cardiac condition such as angina pectoris or myocardial infarction or clinically significant arrhythmia requiring therapy including anticoagulants within the past 6 months or at screening
Resting tachycardia (heart rate of >100 bpm) at screening
Clinically significant uncontrolled hypertension at screening
Cardiac MRI at screening demonstrating infiltrative disease of the myocardium

With a history of documented significant pleural or pericardial effusions, specifically any of the following within 3 months before the start of study treatment:

Pericarditis (any grade)
Pericardial effusion (Grade ≥2)
Non-malignant pleural effusion (Grade ≥2) OR
Malignant pleural effusion (Grade ≥3)
With a history of noncardiogenic pulmonary edema associated with peripheral edema and a history of intravascular hypovolemia associated with antineoplastic therapy.

With chronic or active infection requiring systemic therapy and a history of symptomatic viral infection that is not fully controlled or cured. The following exceptions apply for those with positive serologies of HIV, HBV, or HCV:

With HIV and undetectable viral load and CD4+ T-cell (CD4+) counts ≥350 cells/mL may be enrolled, but must be taking appropriate opportunistic infection prophylaxis, if clinically relevant.
With positive HBV serology are eligible if they have an undetectable viral load and the patient will receive antiviral prophylaxis for potential HBV reactivation per institutional guidelines.
With positive HCV serology are eligible if qPCR for plasma HCV RNA is below the lower limit of detection. Concurrent antiviral HCV treatment per institutional guidelines is allowed.
Have received a live attenuated vaccine within 28 days of the first dose of MT-0169
With a history of Grade ≥2 SIRS/CRS reactions following infusion with any mAbs or CAR T therapy.
With a chronic condition requiring systemic corticosteroids ≥10 mg/day of prednisone or equivalent.
With a known allergy or intolerance to any of the drugs in the study or excipients in the MT-0169 formulation.
Are lactating and breastfeeding or have a positive serum pregnancy test during the screening period or male or female patients of reproductive potential who are not employing effective birth control.
With a concurrent medical or psychiatric illness that would preclude study conduct and assessment including, but not limited to, uncontrolled medical conditions, uncontrolled and active infection, uncontrolled risk of bleeding, uncontrolled diabetes mellitus, pulmonary disease, alcoholic liver disease, or primary biliary cirrhosis.
With a history of hypersensitivity or serious toxic reactions to kanamycin or another aminoglycoside

Study is for people with:

Non Hodgkin Lymphoma

Phase:

Phase 1

Estimated Enrollment:

144

Study ID:

NCT04017130

Recruitment Status:

Active, not recruiting

Sponsor:

Molecular Templates, Inc.

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There are 9 Locations for this study

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University of Southern California
Los Angeles California, 90033, United States
Mayo Clinic - Jacksonville
Jacksonville Florida, 32224, United States
Miami University
Miami Florida, 33136, United States
Northside Hospital
Atlanta Georgia, 30342, United States
Indiana University
Indianapolis Indiana, 46202, United States
Mayo Clinic - Rochester
Rochester Minnesota, 55905, United States
The Ohio State University
Columbus Ohio, 43201, United States
University of Pennsylvania
Philadelphia Pennsylvania, 19104, United States
Vanderbilt University Medical Center- Ingram Cancer Center
Nashville Tennessee, 37203, United States

How clear is this clinincal trial information?

Study is for people with:

Non Hodgkin Lymphoma

Phase:

Phase 1

Estimated Enrollment:

144

Study ID:

NCT04017130

Recruitment Status:

Active, not recruiting

Sponsor:


Molecular Templates, Inc.

How clear is this clinincal trial information?

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