PK,PD, Safety and Tolerability of Multiple Dose Regimens of MT-3724 With Lenalidomide for the Treatment of Patients With Relapsed/Refractory B-Cell Non-Hodgkin's Lymphoma (MT-3724_NHL_003)

• ClinicalTrials.gov Identifier: NCT03645395
• Recruitment Status: Terminated
• First Posted: August 24, 2018
• Last Update Posted: June 16, 2021
• Sponsor: Molecular Templates, Inc.
• Information provided by (Responsible Party): Molecular Templates, Inc.

Study Description

Brief Summary:

The purpose of this study is to evaluate the safety and tolerability of MT-3724 in combination with Lenalidomide in subjects with relapsed or refractory B-Cell NHL.

Condition or disease	Intervention/treatment	Phase
Non-hodgkin Lymphoma	Drug: MT-3724	Phase 2

Detailed Description:

This is a multi-center, open-label two-part study evaluating the safety and tolerability of MT-3724 in combination with Lenalidomide in relapsed or refractory CD20 positive 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 Lenalidomide

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 Lenalidomide. In addition, the PK, PD, immunogenicity and tumor response at the MTD of MT-3724 in combination with Lenalidomide will be more thoroughly evaluated in Part 2.

It is anticipated that up to 64 patients will be enrolled. Treatment will continue until disease progression, withdrawal of consent or any other reason.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 9 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2a Open-label Study to Investigate Safety and Tolerability (Including the Maximum Tolerated Dose), Efficacy, Pharmacokinetics, Pharmacodynamics and Immunogenicity of MT-3724 in Combination With Lenalidomide in Subjects With Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma
• Actual Study Start Date: April 8, 2019
• Actual Primary Completion Date: March 10, 2021
• Actual Study Completion Date: March 10, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: MT-3724 10 mcg/kg-LEN; MT-3724 10 mcg/kg/dose IV for 6 doses over 12 days (M-W-F X 2 weeks) of each 28 day cycle in combination with LEN. If the treatment with MT-3724 is continued beyond Cycle 2, then MT-3724 will be administered weekly (Day 1, 8, 15 and 22) of each 28-day cycle	Drug: MT-3724; Experimental treatment with MT-3724 in combination with LEN therapy.
Experimental: MT-3724 25 mcg/kg-LEN 3x a week; MT-3724 25 mcg/kg/dose IV for 6 doses over 12 days (M-W-F X 2 weeks) of each 28 day cycle in combination with LEN. If the treatment with MT-3724 is continued beyond Cycle 2, then MT-3724 will be administered weekly (Day 1, 8, 15 and 22) of each 28-day cycle	Drug: MT-3724; Experimental treatment with MT-3724 in combination with LEN therapy.
Experimental: MT-3724 20 mcg/kg-LEN 3x a week; MT-3724 20 mcg/kg/dose IV for 6 doses over 12 days (M-W-F X 2 weeks) of each 28 day cycle in combination with LEN. If the treatment with MT-3724 is continued beyond Cycle 2 , then MT-3724 will be administered weekly (Day 1, 8, 15 and 22) of each 28-day cycle	Drug: MT-3724; Experimental treatment with MT-3724 in combination with LEN therapy.
Experimental: MT-3724 25 mcg/kg-LEN 2x a week; MT-3724 25 mcg/kg dose IV for 4 doses (days 1, 5, 8 and 12 during cycles 1 and 2) of each 28 day cycle in combination with LEN and weekly during cycles 3 and beyond (days 1, 8, 15 and 22).	Drug: MT-3724; Experimental treatment with MT-3724 in combination with LEN therapy.
Experimental: MT-3724 50 mcg/kg-LEN; MT-3724 50 mcg/kg dose IV for 4 doses (days 1, 5, 8 and 12 during cycles 1 and 2) of each 28 day cycle in combination with LEN and weekly during cycles 3 and beyond (days 1, 8, 15 and 22).	Drug: MT-3724; Experimental treatment with MT-3724 in combination with LEN therapy.

Outcome Measures

Primary Outcome Measures :

1. Determine the tolerability of MT-3724 in combination with Lenalidomide for the Treatment of Patients With Relapsed/Refractory Non-Hodgkin's Lymphoma [ Time Frame: Through study completion, anticipated to be approximately 1 year ]
   Incidence of AEs, including DLTs, inclusive of physical exam findings, laboratory abnormalities, and/or subject-reported symptoms
2. Determine the safety of MT-3724 in combination with Lenalidomide for the Treatment of Patients With Relapsed/Refractory Non-Hodgkin's Lymphoma [ Time Frame: Through study completion, anticipated to be approximately 1 year ]
   Incidence of AEs, including DLTs, inclusive of physical exam findings, laboratory abnormalities, and/or subject-reported symptoms

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 101 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

- Subjects must meet ALL the following criteria to be eligible for the study.

1. Be adequately informed about the study and fully consent to participation as demonstrated by signing the written ICF before any screening procedure.
2. Be aged ≥18 years years on the date of signing the informed consent form.

3. Have relapsed or refractory CD20 positive B-cell NHL that, in the investigator's opinion, could benefit from MT-3724+LEN therapy. Subjects must have proof of CD20 positive NHL either by:

   1. Historical biopsies (obtained with diagnosis of relapsed or refractory disease), or

   2. Fresh biopsies.

      • Bone marrow biopsy
      • Excisional lymph node biopsy
   3. Core biopsy of any involved organ; all are acceptable methods; FNA not acceptable
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 (MTD expansion cohort).

5. Have received all available approved therapies for NHL, one of which should be anti-CD20 based therapy.

   1. Subjects whose prior therapy includes chimeric antigen receptor t-cell (CAR-T) cell therapy are eligible.
   2. Subjects who underwent stem cell transplant (SCT) >100 days for autologous SCT or >180 days for allogeneic SCT before study drug administration and exhibited a full hematological recovery (consistent with the existing inclusion criteria requirements and without PRBC or platelet transfusions within 2 weeks of C1D1) prior to relapse are eligible.

6. Have bi-dimensionally measurable disease by Lugano Classification for NHL:

   1. >1.5 cm LDi for lymph nodes
   2. >1.0 cm LDi for extra nodal disease.
7. Eastern Cooperative Oncology Group (ECOG) performance status of ≤2

8. Have adequate bone marrow function, as determined by all the following:

   1. Absolute neutrophil count (ANC) ≥1,000/mm³
   2. Platelet count ≥50,000 mm³
   3. Hemoglobin ≥8g/dL

9. Have adequate kidney function, creatinine clearance (CLcr) to be ≥50mL/min either measured or assessed by using the Cockcroft-Gault formula.

   a. At the investigator's discretion, the eGFR result ≤50 mL/min may be verified by measurement of CLcr based on the 24-hour urine collection. Subjects with CLcr ≥50 mL/min will be eligible irrespective of the eGFR result.

10. Have adequate hepatic function, as determined by:

    1. Total bilirubin ≤1.5 x upper limit normal (ULN), or direct bilirubin ≤1.5 x ULN for subjects with elevated total bilirubin secondary to Gilbert's Syndrome) and
    2. Aspartate aminotransferase (AST) ≤3 x ULN (or ≤5 x ULN if liver involvement) and
    3. Alanine aminotransferase (ALT) ≤3 x ULN (or ≤5 x ULN if liver involvement)

11. Have adequate coagulation, as determined by:

    1. International Normalized Ration (INR) or Prothrombin Time (PT) ≤1.5 x ULN (unless on therapeutic anticoagulants)
    2. Activated partial thromboplastin time (aPTT) ≤1.5 x ULN (unless on therapeutic anticoagulants)
12. Albumin ≥ 3.0 g/dL
13. Women of reproductive potential must have a negative pregnancy test on 2 occasions during the screening period (within 10-14 days and within 24 hours before the start of treatment). Women not of reproductive potential are female subjects who are postmenopausal(>1 year since last menstrual cycle) or permanently sterilized (e.g., hysterectomy, bilateral salpingectomy).
14. Males must agree to always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking LEN and for up to 4 weeks after discontinuing LEN, even if they have undergone a successful vasectomy. Male subjects taking LEN must not donate sperm.
15. Subjects of reproductive potential and their partners must agree to either to abstain continuously from heterosexual intercourse or to use 2 methods of reliable birth control simultaneously to begin 4 weeks prior to initiating treatment with LEN until 28 days after the last dose of MT-3724 or LEN. The investigator or a designated associate should advise the subject how to achieve adequate contraception. The following birth control methods may be considered: one highly effective form of contraception - tubal ligation, intrauterine device (IUD), hormonal (birth control pills, injections, hormonal patches, vaginal rings, or implants), or partner's vasectomy, and one additional effective contraceptive method - male latex or synthetic condom, diaphragm, or cervical cap.
16. Subjects must have a life expectancy of >3 months from the start of treatment.

Exclusion Criteria:

• Subjects who meet any of the following criteria must be excluded from the study.

Medical and surgical history

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

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

   1. Had radiotherapy or another appropriate therapy for the brain or spinal metastases; concurrent prophylactic treatment is allowed.
   2. Neurological symptoms must be stable and no worse than grade 2
   3. Have evidence of stable brain or spinal disease on computer topography (CT) or magnetic resonance imaging (MRI) scan obtained within 4 weeks of signing the ICF and compared with prior imaging results.
   4. Do not require chronic steroid therapy, or if applicable, have been stable on steroid dose of no more than prednisone 20mg/day or equivalent by C1D1.
3. Current evidence of Graft versus Host Disease.
4. Current evidence of Common Terminology Criteria for Adverse Events (CTCAE) Grade >1 toxicity (before the start of treatment, except for hair loss, and those Grade 2 toxicities listed as permitted in other eligibility criteria).
5. Current evidence of incomplete recovery from surgery or radiotherapy before the start of treatment, or planned surgery or radiotherapy at any time during the study until the EoT Visit, except minor elective interventions deemed acceptable by the investigator.

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

   a. Subjects 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

7. Current evidence of significant cardiovascular disease including, but not limited to the following conditions:

   1. Unstable angina (symptoms of angina at rest) or new-onset angina within ≤3 months before the start of treatment.
   2. Arterial thrombosis or pulmonary embolism within ≤3 months before the start of treatment.
   3. Myocardial infarction or stroke within ≤3 months before the start of treatment.
   4. Pericarditis (any CTCAE grade), pericardial effusion (CTCAE Grade ≥2), non malignant pleural effusion (CTCAE Grade ≥2) or malignant pleural effusion (CTCAE Grade ≥3).
   5. Congestive heart failure New York Heart Association (NYHA) Class III or IV at screening or left ventricular ejection fraction (LVEF) <45%, assessed by Echo or multiple-gated acquisition (MUGA) scan within 1 month before starting study treatment. (inclusion of subjects with LVEF between 40%-45% should be discussed and approved by the sponsor). Echo or MUGA scan performed within 6 months before screening and at least 28 days after the last cancer therapy is acceptable provided the subject has not received any potential cardiotoxic agents since then.
   6. Cardiac arrhythmia requiring anti-arrhythmic therapy at Screening. Subjects receiving digoxin, calcium channel blockers, or beta-adrenergic blockers are eligible at the investigator's discretion after consultation with medical monitor if the dose has been stable for ≥2 weeks before the start of treatment with MT-3724. Subjects with sinus arrhythmia and infrequent premature ventricular contractions are eligible at the investigator's discretion.
8. QT interval corrected according to Fridericia's formula (QTcF) >480 ms, determined as the average from three QTcF values on the triplicate electrocardiogram (ECG) obtained at Screening.

9. Current evidence of uncontrolled HIV, HBV or 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 subjects with positive viral serology:

   1. Subjects with HIV and an undetectable viral load and CD4+ T-cells counts ≥350 cells/microliter may be enrolled, but must be taking appropriate opportunistic infection prophylaxis, if clinically relevant.
   2. Subjects with positive HBV serology are eligible if they have an undetectable viral load and the subject will receive antiviral prophylaxis for potential HBV reactivation-per institutional guidelines.
   3. Subjects with positive HCV serology are eligible if quantitative PCR for plasma HCV RNA is below the lower limit of detection. Concurrent antiviral HCV treatment per institutional guidelines is allowed.
10. Women who are pregnant or breastfeeding.
11. History or current evidence of hypersensitivity to any of the study drugs, or of current hypersensitivity requiring systemic steroids at doses >20 mg/day prednisone equivalent.

12. History or current evidence of any other medical or psychiatric condition or addictive disorder, or laboratory abnormality that, in the opinion of the investigator, 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.

    Prior treatments

13. Prior treatment with MT-3724.

14. Received anti-CD20 monoclonal antibody (Mab) therapy within the following periods before the start of treatment

    1. Rituximab (Rituxan® RTX): 84 days; if a subject had received RTX within 37 Weeks before the start of treatment, then a serum RTX level must be negative (<500 ng/mL) at screening.
    2. Obinutuzumab (Gazyva®): 184 days
    3. Ofatumumab (Arzerra®): 88 days
15. Received therapy for NHL (except the anti-CD20 Mab therapies listed above and radioimmunoconjugates) within 4 weeks before the start of treatment.
16. 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.

17. 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 may be permitted at the investigator's discretion after consultation with the medical monitor.

18. Received any live vaccines within 4 weeks before of the start of treatment, unless the investigator believes the benefits outweigh the risks, after approval with the sponsor.
19. Require use of systemic immune modulators during study treatment. a. Systemic immune modulators include but are not limited to systemic corticosteroids at doses >20 mg/day or prednisone equivalent, cyclosporine and tacrolimus.

Contacts and Locations

Locations

United States, California

Innovative Clinical Research Institute

Whittier, California, United States, 90603

United States, Florida

Boca Raton Clinical Research

Plantation, Florida, United States, 33322

United States, Illinois

Rush University

Chicago, Illinois, United States, 60612

United States, Maryland

University of Maryland

Baltimore, Maryland, United States, 21201

United States, Texas

University of Texas Southwestern

Dallas, Texas, United States, 75390

Sponsors and Collaborators

Molecular Templates, Inc.

More Information

• Responsible Party: Molecular Templates, Inc.
• ClinicalTrials.gov Identifier: NCT03645395
• Other Study ID Numbers: MT-3724_NHL_003
• First Posted: August 24, 2018
• Last Update Posted: June 16, 2021
• Last Verified: June 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Lymphoma; Lymphoma, Non-Hodgkin; Lymphoma, B-Cell; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases