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
Overview
- Phase
- Phase 2
- Intervention
- DTRM-555
- Conditions
- Relapsed Chronic Lymphocytic Leukemia
- Sponsor
- Zhejiang DTRM Biopharma
- Enrollment
- 55
- Locations
- 6
- Primary Endpoint
- Complete Responses (CR) and Partial Responses (PR) with DTRM-555 in the five disease-specific cohorts
- Status
- Terminated
- Last Updated
- last year
Overview
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).
Investigators
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
- •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.
Exclusion Criteria
- •Received prior systemic anticancer treatment within the following time frames:
- •Chemotherapy, immunotherapy, radiotherapy or any other investigational therapy within 21 days prior to starting study treatment.
- •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:
- •Aspartate transaminase (AST) or alanine transaminase (ALT) \> 2.5 x upper limit of normal (ULN); for patients with liver involvement, \> 5 x ULN
- •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)
- •Alkaline phosphatase \> 2.5 x ULN
- •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
Arms & Interventions
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
Intervention: DTRM-555
Outcomes
Primary Outcomes
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 Outcomes
- 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(24 hours)
- Treatment-Emergent Adverse Events (AEs) in the five disease-specific cohorts(24 months)
- Overall Response Rate (ORR) with DTRM-555 in the five disease-specific cohorts(6, 12 and 24 months)