Phase II Clinical Trial of Drug Combinations Guided by Ex-vivo Testing in Patients With Relapsed/Refractory T-cell Lymphoma (COMBINEX-T)
A Multicentre Phase II Clinical Trial of Drug Combinations Guided by Ex-vivo Testing in Patients With Relapsed/Refractory T-cell Lymphoma
National University Hospital Singapore
36 participants
Nov 11, 2025
Interventional
Conditions
Summary
This is a multicentre phase II clinical trial evaluating the efficacy of drug combinations guided by ex-vivo drug sensitivity testing using the Quadratic Phenotypic Optimisation Platform (QPOP) in patients with relapsed/refractory peripheral T-cell lymphoma (RR PTCL). We hypothesize that QPOP analysis of patient-derived tumour cells can be used to derive effective drug combinations for the treatment of RR PTCL. Using an 19-drug search set consisting of agents with published activity in PTCL, we predict that a viable drug combination recommendation can be identified in ~80% of patients, and that QPOP based therapy will result in an improvement in overall response rate (ORR) by 20% above the published ORR. For those doublets with established RP2D published, these doses will be used. For novel doublets, they will be dosed at 75% of the RP2D for each drug. Patients who achieve complete response (CR) may be taken to transplant if eligible. Non-transplant eligible patients in CR will receive no further treatment. Patients who achieve partial response (PR) may be taken to transplant if eligible. Non-transplant eligible patients in PR will receive up to 6 months of maintenance therapy with the same doublet regimen. Patients who achieve stable disease (SD) may receive up to 6 months of maintenance therapy with the same doublet regimen or be taken off the study if their attending physician deems that a new line of treatment is required. Patients who experience progressive disease (PD) will be taken off the study and their treatment will be directed by their physicians. All patients will be followed up for 5 years after the last patient has completed study treatment.
Eligibility
Inclusion Criteria27
- Patient has provided written informed consent.
- Patient has histologically confirmed peripheral T-cell lymphoma based on WHO
- criteria.
- Relapsed or refractory following 1 or more lines of prior treatment.
- Bi-dimensionally measurable disease, with at least one mass lesion greater than or
- equal to 2 cm in longest diameter.
- Male or female age greater than or equal to 21 years at signing consent.
- Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to
- Adequate organ and haematologic function within 7 days prior to cycle 1 day 1 defined
- by:
- a. ANC greater than or equal to 1 x 109/L and platelet count greater than or equal to
- x109/L; unless due to marrow infiltration or hypersplenism.
- b. Serum aspartate transaminase (AST) or alanine transaminase (ALT) < 5 x upper
- limit of normal (ULN).
- c. Bilirubin < 2.0 x ULN unless due to Gilbert’s syndrome, documented liver
- involvement with lymphoma, or of non-hepatic origin
- d. Calculated creatinine clearance greater than or equal to 30ml/min
- Able to comply with protocol requirements and follow-up procedures.
- Female patients of childbearing potential (FCBP) must be willing to use two methods
- of birth control simultaneously or be surgically sterile or abstain from heterosexual
- activity for at least 28 days before initiation of treatment, during study treatment and at
- least 12 months after the last dose of study treatment. Patients of childbearing
- potential are those who have not been surgically sterilized or have not been free from
- menses for > 24 consecutive months.
- Sexually active males must agree to use a condom during sexual contact with a
- pregnant female or a female of child-bearing potential (FCBP) for the course of the
- study through to 18 months after the last dose of treatment.
Exclusion Criteria12
- Known central nervous system lymphoma or leptomeningeal disease.
- History of other malignancy that could affect compliance with the protocol or interpretation of results.
- Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator’s opinion, could compromise the patient’s safety or put the study outcomes at undue risk.
- Known hypersensitivity to any of the study drugs or their components.
- Has received anti lymphoma therapy other than steroids within 7 days prior to Cycle 1 Day 1.
- Has a known active/uncontrolled bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrolment.
- Presence of positive test results for hepatitis B virus (HBV), hepatitis B surface antigen (HBsAg), or hepatitis C (HCV) antibody:
- Patients who are positive for HCV antibody must be negative for HCV by polymerase chain reaction (PCR) to be eligible for study participation
- Patients with occult or prior HBV infection (defined as positive total hepatitis B core antibody [HBcAb]) may be included if HBV DNA is undetectable. HBsAg positive patients may be included as long as these patients must be willing to receive prophylactic anti-viral therapy and undergo monthly HBV DNA testing during (and for 6 months following completion of) treatment.
- Known HIV infection or a positive result for HIV test performed during screening.
- Receipt of live-virus vaccines within 28 days prior to Cycle 1 Day 1 or need for live-virus vaccines at any time during study treatment.
- Pregnant or lactating or intending to become pregnant during the study.
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Interventions
This study uses the Quadratic Phenotypic Optimisation Platform (QPOP) developed by KYAN Technologies to identify the most effective two-drug combination for relapse or refractory peripheral T-cell lymphoma (RR PTCL). The utility of QPOP as a clinical decision support tool in lymphoma has been previously reported by the study team ( de Mel et al Blood Cancer J 2020, Goh et al Sci Trans Med 2022). QPOP analysis will be performed on fresh tumor biopsy, bone marrow or blood samples (depending on the patient’s site of lymphomatous involvement) to select an optimal two-drug regimen from a panel of 19 drugs chosen based on their established preclinical or clinical activity in PTCL, and human safety data as single agents. These drugs are: 1) Romidepsin 2) Vinorelbine 3) Gemcitabine 4) Bortezomib 5) Etoposide 6) Ceritinib 7) Azacitidine 8) Sorafenib 9) Cyclosporine 10) Cytarabine 11) Oxaliplatin 12) Procarbazine 13) Melphalan 14) Ifosfamide 15) Chlorambucil 16) Pegasparaginase 17) Lenalidomide 18) Venetoclax 19) Ruxolitinib. These drugs will be administered via infusion or taken orally. QPOP is conducted in two stages using samples from the same patient, with stage 1 occurring first followed by stage 2. • Stage 1: A 10- to 12-drug search set will be interrogated, composed of both novel and standard of care therapeutics. An experimental dataset will be built by treating lymphoma cells with drug combinations predetermined by orthogonal composite array design (OACD). • Stage 2: The response dataset from stage 1 will be used to implement the best patient-specific drug combinations using a regression model. Top ranked drug combinations identified by QPOP will be validated through serial dose-response testing. These data will rank the doublet regimens personalized to each patient. Pre-specified drug combinations that are known to have additive toxicity will not be used even if predicted to have efficacy by QPOP. All drug combinations generated by QPOP will undergo review by the attending clinician and the pharmacist before approval for use. All enrolled patients will receive 6 cycles of the same QPOP-recommended treatment. Drug treatment adherence monitored using a dosing diary. Each treatment cycle will last either 21 or 28 days, depending on the recommended drug combination. In addition, patients will undergo PET-CT scan at baseline (prior to treatment), after the second cycle and after the sixth cycle of treatment. All patients will participate in the study for a total of 6 years, including a 5-year follow-up period after the last patient has completed study treatment.
Locations(1)
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ACTRN12626000088347