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Trial record 3 of 5 for:    molecular templates | lymphoma

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

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ClinicalTrials.gov Identifier: NCT03645395
Recruitment Status : Recruiting
First Posted : August 24, 2018
Last Update Posted : September 9, 2019
Sponsor:
Information provided by (Responsible Party):
Molecular Templates, Inc.

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 Refractory Diffuse Large B-Cell Lymphoma Relapsed Diffuse Large B-Cell 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 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 for up to Six 28 day cycles (approximately 6 months)


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 64 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 MTD), 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
Estimated Primary Completion Date : December 17, 2020
Estimated Study Completion Date : July 30, 2022


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
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 50 mcg/kg-LEN
MT-3724 50 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.




Primary Outcome Measures :
  1. Tolerability as measured by number of subjects with dose limiting toxicities [ Time Frame: 28 days ]
    Evaluation of tolerability of MT-3724 measured by number of subjects with dose limiting toxicities (DLTs)

  2. Safety measured by number of subjects with Adverse Events using CTCAE [ Time Frame: 28 days ]
    Safety measured by number of subjects with Adverse Events using CTCAE Version 5.0


Secondary Outcome Measures :
  1. PK as measured by concentrations of free MT-3724 (Maximum Plasma Concentration [Cmax]) [ Time Frame: Dose 1 (Day 1) in Each 28-Day cycle up to 6 cycles, Dose 6 (Day 12) in Cycle 1 only ]
    Evaluation of the pharmacokinetic profile of MT-3724

  2. PK as measured by concentrations of free MT-3724 (Area Under the Curve [AUC]) [ Time Frame: Dose 1 (Day 1) in Each 28-Day cycle up to 6 cycles, Dose 6 (Day 12) in Cycle 1 only ]
    Evaluation of the pharmacokinetic profile of MT-3724

  3. PK as measured by concentrations of free MT-3724 (Time to reach maximum concentration after drug administration [Tmax]) [ Time Frame: Dose 1 (Day 1) in Each 28-Day cycle up to 6 cycles, Dose 6 (Day 12) in Cycle 1 only ]
    Evaluation of the pharmacokinetics profile of MT-3724

  4. PD as measured by tumor response [ Time Frame: Measured one at End of Treatment visit at approximately 6 months ]
    PD as measured by assessment of CD-20 positive status of DLBCL. Evaluation of the Pharmacodynamics profile of MT-3724 by fine needle aspirant of accessible peripheral LN as measured by IHC staining to determine CD 20 positive status of DLBCL in subject who exhibit progressive disease.

  5. Immunogenicity as measured by MT-3724 [anti-drug antibody (ADA) titer and neutralizing antibody (NA)] [ Time Frame: day 1 of each 28 day cycle:At approximately 1 month, 2 months, 3 months, 4 months, 5 months and 6 months ]
    Evaluation of the immunogenicity of MT-3724 {anti-drug antibody (ADA) titer and neutralizing antibody (NA) will be collected.Data for anti-drug antibody (ADA) against MT-3724 will be obtained as the positive or negative.

  6. PD as measured by B-cell count in peripheral blood as determined by flow cytometry measured against MT-3724 serum concentrations at pre-specified time points [ Time Frame: Day 1 in each Cycle, Day 12 of Cycle 1-Cycle 2, Day 15 of Cycle 3 -Cycle 6; each cycle is of 28 Days total of 6 cycles and overall 11 assessments ]
    Evaluation of the Pharmacodynamic profile of MT-3724

  7. PD as measured by by immunophenotype in peripheral blood, as determined by flow cytometry measured against MT-3724 serum concentrations at pre-specified time points [ Time Frame: Day 1 in each Cycle, day 12 of Cycle 1-Cycle 2, Day 15 of Cycle 3 -Cycle 6; each cycle is of 28 days ]
    Evaluation of the Pharmacodynamic profile of MT-3724

  8. Tumor Response as measured by PET or CT scan [ Time Frame: 28 Days ]
    Tumor response to be assessed by the CT scan (PET or CT) of all the automatic regions involved with the measurable disease. Positron emission tomography-computed tomography (PET-CT) should be used in subjects with fluorodeoxyglucose (FDG)-avid tumor histology. Computed tomography (CT) or magnetic resonance imaging (MRI) should be used in subjects with tumor Histology of low or variable FDG avidity. Tumor response in subjects with FDG -avid tumor Histology will be determined using the 5 point scale (5 PS) according to the Lugano Classification for lymphoma (cheson 2014)adjusted according to LYRIC (lymphoma response to immunomudulatory therapy criteria)(Cheson 2016)The objective tumor response rate (ORR) at each time point to based on radiologist's measurement of all evaluable lesions.The ORR representing clinically significant clinical benefit in this study will comprise the Lugano score 1,2,or 3 or the CR or PR)



Information from the National Library of Medicine

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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 informed consent form before any screening procedure.
    2. Men or Women , age 18 years or older Have relapsed or refractory B-cell NHL that, in the investigator's opinion, could benefit from MT-3724+LEN therapy.
    3. At least one histology documented relapse of NHL by:

      1. Bone marrow biopsy (FNA is not acceptable)
      2. Excisional lymph node biopsy or
      3. Core biopsy of any involved organ (FNA not acceptable)
      4. CD20-positive histology must have been confirmed at any time during NHL disease course and documented in the medical history.
      5. If no histology is available after any relapse the investigator can consult the medical monitor to discuss if the patient can be included
    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 (expansion cohort)
    5. Have received all available approved therapies for NHL. Those subjects who are ineligible for approved therapies in the opinion of the investigator, or have refused such therapies, will be eligible.
    6. Have measurable disease by Lugano Classification for NHL (see Appendix 4):

      1. >1.5 cm longest diameter (LDi) for lymph nodes
      2. >1.0 cm LDi for extra nodal disease.
    7. Eastern Cooperative Oncology Group (ECOG) performance score 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
    9. Have adequate kidney function, assessed by the estimated glomerular filtration rate (eGFR) ≥60 mL/min calculated by the CPK-EPI equation.

      a. At the investigator's discretion, the eGFR result <60 mL/min may be verified by measurement of creatinine clearance (CLcr) based on the 24-hour urine collection. Subjects with CLcr ≥60 mL/min will be eligible irrespective of the eGFR result.

    10. Have adequate hepatic function, as determined by:

      1. Total bilirubin ≤1.5 x ULN, or ≤3 x ULN for subjects with Gilbert's Syndrome) and
      2. AST ≤3 x ULN and
      3. ALT ≤3 x ULN
    11. Have adequate coagulation, as determined by:

      1. INR or PT ≤1.5 x ULN
      2. PTT ≤1.5 x ULN
    12. Have adequate serum albumin, as determined by:

      a. 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 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 patients 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, 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.

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 or any previous cancer curatively treated >2 years before the start of treatment.
  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
    2. Have no neurological symptoms (excluding Grade ≤2 neuropathy)
    3. Have stable brain or spinal disease on the CT or MRI scan within 1 month of enrollment
    4. Do not require chronic steroid therapy
  3. History of allogeneic hematopoietic stem cell transplant within 180 days before the start of treatment.
  4. Current evidence of acute or chronic Graft versus Host Disease.
  5. Current evidence of CTCAE Grade >1 toxicity (except for hair loss, and those toxicities listed in other eligibility criteria) before the start of treatment.
  6. Current evidence of incomplete recovery from surgery before the start of treatment, or planned surgery at any time during the study until the EoT Visit, except minor elective interventions deemed acceptable by the investigator.
  7. History or current evidence of significant (CTCAE Grade ≥2) infection or wound within 4 weeks before the start of treatment.
  8. History or 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 (NYHA Class III or IV) at screening or LVEF <45%, assessed by Echo or MUGA scan within 1 month before starting study treatment. (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).
    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. Subjects with sinus arrhythmia and infrequent premature ventricular contractions are eligible at the investigator's discretion.
  9. QTcF (Fridericia) >480 ms, determined as the average from three QTcF values on the triplicate ECG obtained at screening.
  10. Current evidence of seropositive status for HIV, hepatitis B (positive for HBsAg or anti-HBsAg and anti-HBcAg antibodies) or hepatitis C (positive for anti-HCV antibody or HCV-RCV-RNA quantitation) as assessed by the applicable serology testing at screening.

    1. Serology testing is not required if seronegativity is documented in the medical history and there are no clinical signs suggestive of HIV or hepatitis infection.
    2. Subjects with positive HBV serology are eligible if quantitative PCR for plasma HBV-DNA is negative and the subject will be receiving prophylaxis for potential HBV reactivation.
    3. Subjects with positive HCV serology are eligible if quantitative PCR for plasma HCV RNA is negative.
  11. Women who are pregnant or breastfeeding.
  12. 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.
  13. 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

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

    1. Rituximab (Rituxan®): 84 days; if a subject had received rituximab within 37 Weeks before the start of treatment, then a serum rituximab 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) 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 is allowed at the investigator's discretion.

  18. Received any vaccines within 28 days of the start of treatment, or likely to require vaccines at any time from the start of treatment until 28 days after the last dose of MT-3724. Injectable flu vaccine (inactivated or recombinant) is permitted at the investigator's discretion.
  19. Received systemic immune modulators within 2 weeks before the start of treatment

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03645395


Contacts
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Contact: Tara Lehner, MS, PMP 215- 586-0118 tara.lehner@mtem.com
Contact: Kristina Dabovic, PharmD 862-204-7184 kristina.dabovic@mtem.com

Locations
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United States, Florida
Boca Raton Clinical Research Recruiting
Plantation, Florida, United States, 33322
Contact: Jason Tache, MD         
United States, Illinois
Rush University Recruiting
Chicago, Illinois, United States, 60612
Contact: Tami Burge       tonya_m_burge@rush.edu   
Sponsors and Collaborators
Molecular Templates, Inc.

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Responsible Party: Molecular Templates, Inc.
ClinicalTrials.gov Identifier: NCT03645395     History of Changes
Other Study ID Numbers: MT-3724_NHL_003
First Posted: August 24, 2018    Key Record Dates
Last Update Posted: September 9, 2019
Last Verified: August 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Lymphoma
Lymphoma, Non-Hodgkin
Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lenalidomide
Immunologic Factors
Physiological Effects of Drugs
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors
Antineoplastic Agents