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Study of a Triple Combination Therapy, DTRM-555, in Patients With R/R CLL or R/R Non-Hodgkin's Lymphomas

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04305444
Recruitment Status : Recruiting
First Posted : March 12, 2020
Last Update Posted : April 29, 2022
Sponsor:
Information provided by (Responsible Party):
Zhejiang DTRM Biopharma

Brief Summary:
Targeted drug therapies have greatly improved outcomes for patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma. However, single drug therapies have limitations, therefore, the current study is evaluating a novel oral combination of targeted drugs as a way of overcoming these limitations. This study will determine the efficacy of the triple combination therapy, DTRM-555, in patients with R/R CLL or R/R non-Hodgkin's lymphoma.

Condition or disease Intervention/treatment Phase
Relapsed Chronic Lymphocytic Leukemia Refractory Chronic Lymphocytic Leukemia Diffuse Large B Cell Lymphoma Follicular Lymphoma Richter's Transformation Drug: DTRM-555 Phase 2

Detailed Description:

This study is being conducted in three parts: Phase Ia, Phase Ib and Phase II, disease-specific expansion cohorts. Phase Ia explored escalating doses of a monotherapy of a novel Bruton's Tyrosine Kinase (BTK) inhibitor, DTRMWXHS-12. Phase Ib explored two combination therapies, DTRM-505 (DTRMWXHS-12 and everolimus) and DTRM-555 (DTRMWXHS-12, everolimus and pomalidomide).

The current Phase II study will further examine the investigational triple combination treatment, DTRM-555 for efficacy and safety. The study is being conducted in five disease-specific cohorts: Activated B-Cell (ABC) Diffuse Large B-Cell Lymphoma, Germinal Center B-Cell (GCB) Diffuse Large B-Cell Lymphoma, Richter's Transformation, transformed Follicular Lymphoma, and relapsed or refractory Chronic Lymphocytic Leukemia.

The Primary Objective of the Phase II study is to determine the efficacy of the triple combination therapy, DTRM-555, in the five disease-specific cohorts. The Secondary Objectives are (1) to determine the safety of DTRM-555 in the cohorts and (2) to obtain the pharmacokinetics of DTRM-555 (i.e., DTRMWXHS-12, everolimus and pomalidomide).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: All patients, regardless of disease-specific cohort, will receive the same dose of DTRM-555. There are two stages to the study, and there is the potential for 120 patients in total (potentially 24 patients in each of the 5 cohorts) to participate in the study.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Expansion Cohorts Studies of a Novel Triple Combination Therapy, DTRM-555, in Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia or Relapsed/Refractory Non-Hodgkin's Lymphomas
Actual Study Start Date : April 24, 2020
Estimated Primary Completion Date : March 2024
Estimated Study Completion Date : March 2024


Arm Intervention/treatment
Experimental: Disease-specific cohorts
Participants will be administered the oral triple-combination therapy, DTRM-555 (comprised of 200mg of DTRMWXHS-12, 5mg of everolimus and 2mg of pomalidomide), once-daily for 21 consecutive days every 28 days
Drug: DTRM-555
Oral once-daily administration
Other Names:
  • DTRMWXHS-12
  • everolimus
  • pomalidomide




Primary Outcome Measures :
  1. Complete Responses (CR) and Partial Responses (PR) with DTRM-555 in the five disease-specific cohorts [ Time Frame: 24 months ]
    Response in lymphoma patients will be assessed according to Lugano 2014 criteria guidelines for response assessment of Hodgkin and non-Hodgkin lymphoma. Response in CLL patients will be assessed according to International Workshop on CLL (iwCLL) 2018 criteria for treatment of CLL.


Secondary Outcome Measures :
  1. Treatment-Emergent Adverse Events (AEs) in the five disease-specific cohorts [ Time Frame: 24 months ]
    Percentage of participants with Treatment-Emergent Adverse Events (AEs)

  2. Overall Response Rate (ORR) with DTRM-555 in the five disease-specific cohorts [ Time Frame: 6, 12 and 24 months ]
    Response in lymphoma patients will be assessed according to Lugano 2014 criteria guidelines for response assessment of Hodgkin and non-Hodgkin lymphoma. Response in CLL patients will be assessed according to iwCLL 2018 criteria for treatment of CLL.

  3. Plasma or blood concentration versus time profiles of DTRMWXHS-12, everolimus and pomalidomide will be evaluated to determine key pharmacokinetic parameters for the three drugs [ Time Frame: 24 hours ]
    Plasma or blood concentration versus time profiles of DTRMWXHS-12, everolimus and pomalidomide will be evaluated to determine Area Under the Curves (AUC)

  4. Plasma or blood concentration versus time profiles of DTRMWXHS-12, everolimus and pomalidomide will be evaluated to determine key pharmacokinetic parameters for the three drugs [ Time Frame: 24 hours ]
    Plasma or blood concentration versus time profiles of DTRMWXHS-12, everolimus and pomalidomide will be evaluated to determine Maximum Observed Plasma or Blood Concentrations (Cmax)

  5. Plasma or blood concentration versus time profiles of DTRMWXHS-12, everolimus and pomalidomide will be evaluated to determine key pharmacokinetic parameters for the three drugs [ Time Frame: 24 hours ]
    Plasma or blood concentration versus time profiles of DTRMWXHS-12, everolimus and pomalidomide will be evaluated to determine the Times to Reach Cmax (tmax)

  6. Plasma or blood concentration versus time profiles of DTRMWXHS-12, everolimus and pomalidomide will be evaluated to determine key pharmacokinetic parameters for the three drugs [ Time Frame: 24 hours ]
    Plasma or blood concentration versus time profiles of DTRMWXHS-12, everolimus and pomalidomide will be evaluated to determine Elimination Half-Lives (t1/2)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must provide written informed consent.
  • Patients with a diagnosis of R/R CLL or other B-cell neoplasms (i.e., ABC DLBCL, GCB DLBCL, Richter's transformation and tFL) who have no available approved therapies, or patients with a diagnosis of non-Hodgkin's lymphoma, which has relapsed and/or is refractory to standard therapy.

    a. Patients with R/R CLL must have been exposed to Bruton's tyrosine kinase (BTK) or B-Cell CLL/Lymphoma 2 (BCL2) inhibitor-based therapy in prior lines of therapy but must not have known Cys481 resistance mutation prior to study enrollment.

  • Age ≥ 18 years.
  • Life expectancy greater than 12 weeks.
  • Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
  • Ability to swallow and retain capsules and/or tablets.
  • Absence of uncontrolled intercurrent illnesses, including uncontrolled infections, cardiac conditions, or other organ dysfunctions.
  • If the patient consents to an optional tumor biopsy, he/she must have a tumor that can be safely biopsied and undergo a baseline tumor biopsy procedure, or be willing to provide available archival tissue collected within 6 months of signing the Informed Consent Form (ICF), and one post-Cycle 1 treatment biopsy.
  • Patients must have at least one target lesion according to Lugano Classification. Patients with R/R CLL are exempt from this requirement.
  • Women of child-bearing potential must have a negative serum or urine pregnancy test.
  • Women of child-bearing potential must agree to use 2 reliable methods of contraception beginning 4 weeks prior to the initiation of treatment, during therapy, and for at least 4 weeks after the last drug administration.
  • Men must agree to use a latex or synthetic condom during sexual contact with a pregnant female or a female of child-bearing potential, for the duration of the study and for at least 4 weeks after the last drug administration, even if they have undergone a successful vasectomy.

Exclusion Criteria:

  • Received prior systemic anticancer treatment within the following time frames:

    1. Chemotherapy, immunotherapy, radiotherapy or any other investigational therapy within 21 days prior to starting study treatment.
    2. Targeted therapies within 5 biological half-lives prior to starting study treatment.
  • Patients with active infections requiring therapy are not eligible for entry into the study until resolution of the infection; however, patients on prophylactic antibiotics, antifungals or antivirals are eligible for entry into the study.
  • Pregnant or lactating individuals.
  • Impaired hepatic or renal function as demonstrated by any of the following laboratory values:

    1. Aspartate transaminase (AST) or alanine transaminase (ALT) > 2.5 x upper limit of normal (ULN); for patients with liver involvement, > 5 x ULN
    2. Total bilirubin > 1.5 x ULN (Patients with a history of Gilbert's syndrome may participate if total bilirubin is less than or equal to 3 x ULN and the AST/ALT and alkaline phosphatase meet the protocol-specified levels for eligibility)
    3. Alkaline phosphatase > 2.5 x ULN
    4. Glomerular filtration rate < 50 mL/min, as assessed using the standard methodology at the investigating center (i.e., Cockcroft-Gault), or serum creatinine > 1.5 x ULN
  • International normalized ratio (INR) > 1.5 or other evidence of impaired hepatic synthesis function.
  • Absolute neutrophil count < 1.0 x 109/L or platelets < 100 x 109/L, unless due to disease-related bone marrow impairment as confirmed by bone marrow biopsy during screening or due to standard of care treatment within 2 months prior to signing of informed consent. Patients with bone marrow impairment will be excluded if their absolute neutrophil count (ANC) is < 0.5 x 109/L and platelets < 50 x 109/L.
  • Previous allogeneic bone marrow transplant is restricted, unless transplant was greater than 3 months prior and there is no evidence of acute or chronic graft versus host disease.
  • Central nervous system involvement with malignancy.
  • Patients who have poorly controlled diabetes mellitus or whose glucose values cannot be controlled with medical treatment.
  • Current malignancies of another type, with the exception of adequately treated in situ cervical cancer and basal cell skin cancer, squamous cell carcinoma of the skin or other malignancies with no evidence of disease for 2 years or more.
  • Known history of human immunodeficiency virus (HIV) or active with hepatitis C virus (HCV) or hepatitis B virus (HBV). Subjects who are positive for hepatitis B core antibody, hepatitis B surface antigen, or hepatitis C antibody must have a negative polymerase chain reaction (PCR) result before enrollment. Those who are PCR positive will be excluded.
  • Documented or known bleeding disorder.
  • Requirement for anticoagulation treatment that increases INR or activated partial thromboplastin time above the normal range (low molecular weight heparin and heparin line flush allowed).
  • Patients requiring the use of strong CYP3A4, CYP1A2, or P-gp inhibitors.
  • Patients with a significant cardiovascular disease or condition, including:

    1. myocardial infarction within 6 months of study entry,
    2. New York Heart Association Class III or IV heart failure,
    3. uncontrolled dysrhythmias or poorly controlled angina,
    4. history of serious ventricular arrhythmia (ventricular fibrillation or ventricular tachycardia, ≥ 3 beats in a row) and/or risk factors (e.g., heart failure, hypokalemia, or family history of Long QT Syndrome),
    5. baseline prolongation of QT/QTc interval (repeated demonstration of corrected QT interval (QTc) ≥ 450 msec for men and 470 msec for women), and
    6. left ventricular ejection fraction (LVEF) < 45% by multiple gated acquisition (MUGA) and /or echocardiogram (ECHO).

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): NCT04305444


Contacts
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Contact: Wei He, PhD (215) 337-3168 wei.he@dtrmbiopharma.com

Locations
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United States, Arizona
Mayo Clinic Recruiting
Phoenix, Arizona, United States, 85054
Contact: Clinical Trials Referral Office    855-776-0015      
Principal Investigator: Allison Rosenthal, DO         
United States, Connecticut
Yale - Smillow Cancer Hospital Recruiting
New Haven, Connecticut, United States, 06511
Contact: Hematology Program    203-200-4363      
Principal Investigator: Scott Huntington, MD         
United States, Florida
Mayo Clinic Recruiting
Jacksonville, Florida, United States, 32224
Contact: Clinical Trials Referral Office    855-776-0015      
Principal Investigator: Han Tun, MD         
United States, Minnesota
Mayo Clinic Recruiting
Rochester, Minnesota, United States, 55905
Contact: Clinical Trials Referral Office    855-776-0015      
Principal Investigator: Wei Ding, MBBS, PhD         
United States, New York
Memorial Sloan Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Patient Access Services    800-525-2225      
Principal Investigator: Anthony Mato, MD         
United States, North Carolina
Duke Cancer Institute Recruiting
Durham, North Carolina, United States, 27710
Contact: Duke Recruitment Innovation Center    919-681-5698      
Principal Investigator: Danielle Brander, MD         
United States, Pennsylvania
University of Pennsylvania Abramson Cancer Center Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Abramson Center Clinical Trial Information Center    855-216-0098      
Principal Investigator: Stephen J Schuster, MD         
United States, Tennessee
VA Medical Center - Memphis Recruiting
Memphis, Tennessee, United States, 38104-2127
Contact: VA Medical Center - Memphis    901-523-8990      
Principal Investigator: Alva B Weir, MD         
Sponsors and Collaborators
Zhejiang DTRM Biopharma
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Responsible Party: Zhejiang DTRM Biopharma
ClinicalTrials.gov Identifier: NCT04305444    
Other Study ID Numbers: DTRM-555_001
First Posted: March 12, 2020    Key Record Dates
Last Update Posted: April 29, 2022
Last Verified: April 2022

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Zhejiang DTRM Biopharma:
B-Cell Lymphoma
Diffuse Large B Cell Lymphoma
Everolimus
Follicular Lymphoma
Immunosuppressive Agents
Leukemia
B-Cell Leukemia
Chronic Lymphocytic Leukemia
Lymphatic Diseases
Lymphoma
Malignant Lymphoma
Non-Hodgkin Lymphoma
Lymphoproliferative Disorders
Neoplasms
Tyrosine Protein Kinase
Bruton's Tyrosine Kinase Inhibitor
Pomalidomide
Additional relevant MeSH terms:
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Lymphoma
Leukemia
Lymphoma, Follicular
Lymphoma, Non-Hodgkin
Leukemia, Lymphoid
Lymphoma, B-Cell
Leukemia, Lymphocytic, Chronic, B-Cell
Lymphoma, Large B-Cell, Diffuse
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Everolimus
Pomalidomide
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors