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

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Brief Title

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

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

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.
    

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).
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Complete Responses (CR) and Partial Responses (PR) with DTRM-555 in the five disease-specific cohorts

Secondary Outcome

 Treatment-Emergent Adverse Events (AEs) in the five disease-specific cohorts

Condition

Relapsed Chronic Lymphocytic Leukemia

Intervention

DTRM-555

Study Arms / Comparison Groups

 Disease-specific cohorts
Description:  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

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

120

Start Date

April 24, 2020

Completion Date

March 2024

Primary Completion Date

March 2024

Eligibility 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).
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

, (215) 337-3168, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT04305444

Organization ID

DTRM-555_001


Responsible Party

Sponsor

Study Sponsor

Zhejiang DTRM Biopharma


Study Sponsor

, , 


Verification Date

April 2022