Combination of Mitoxantrone Hydrochloride Liposome with Cyclophosphamide, Vincristine and Prednisone (CMOP) in Treatment-Naïve Patients with Peripheral T-Cell Lymphoma: A Multicenter, Open-Label, Single-Arm, Phase Ib Clinical Trial

Background: Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of lymphomas accounting for 25% to 30% of non-Hodgkin lymphomas in China. Although CHOP remains backbone of frontline treatment in PTCL, outcomes are typically poor. Front-line treatment with brentuximab vedotin plus CHP only provided moderate improvement in CD30-positive PTCL. Therefore, the development of novel agents for this population is still urgently needed. In 2020 ASH annual meeting (Abstracts 42), we reported mitoxantrone hydrochloride liposome (PLM60) monotherapy yielded effective antitumor activity, durable response with mild toxicity in patients with relapsed or refractory PTCL for the first time. This trial aimed to explore the safety, efficacy and pharmacokinetics (PK) of PLM60 plus cyclophosphamide, vincristine and prednisone in patients with treatment-naïve PTCL (TN-PTCL).

Methods: Patients aged 18-75 years with histologically confirmed treatment-naïve PTCL (including PTCL-NOS, AITL, ALCL- ALK+/-; other subtypes that investigators consider to be appropriate), ECOG performance score 0-1 and avid-FDG PTCL by PET/CT were recruited. Main exclusion criteria were patients with ENKTL, MF/SS, primary cutaneous-ALCL and ATLL, central nervous system involvement, hemophagocytic syndrome. This study consisted of two parts. In part 1, 3+3 dose-escalation design with four dose levels of PLM60 (12, 15, 18 and 21 mg/m²) was used to identify the MTD, DLT and recommended Phase II dosage (RP2D) of PLM60 plus cyclophosphamide (750 mg/m²), vincristine (1.4 mg/m² with maximum dose of 2 mg) on day 1 and prednisone 100 mg orally administered on day 1-5 (CMOP) of every cycle (28 days) for 6 cycles. Part 2 was dose expansion at the RP2D. The primary endpoints were safety. Adverse events were defined according to the CTCAE 5.0. The secondary endpoint was efficacy including complete response (CR) rate, duration of complete remission (DoCR), objective response rate (ORR) and progression-free survival (PFS) assessed according to Lugano 2014 criteria and PK profile. This trial is registered at ClinicalTrials.gov (NCT04548700).

Results: At the cut-off data of June 23, 2022, 31 patients were screened in the 6 institutions in China, of which 26 eligible patients (19 males) with a median age of 51.5 (range, 28-70) were enrolled in phase Ib study. Enrolled patients included the following PTCL subtypes: AITL (53.8%), PTCL-NOS (15.4%), ALCL-ALK+ (7.7%), ALCL-ALK- (7.7%) and other subtypes (15.4%). 10 patients (38.5%) presented with B symptom and 20 patients (76.9%) were at the stage III or IV. No dose-limiting toxicities occurred, RP2D was 18 mg/m². Treatment-related adverse events (TRAEs) of any grade occurred in all 26 patients, in which 22 (84.6%) were ≥ grade 3. The most common ≥ grade 3 TRAEs was neutropenia (73.1%), leucopenia (73.1%), lymphocytopenia (38.5%), thrombocytopenia (11.5%), febrile neutropenia (11.5%), infectious pneumonia (7.7%), anemia (7.7%).

After a median follow-up of 10.8 (range 1.6-16.9) months, 25 patients were evaluable for response. CR rate and ORR of the whole cohort were 52.0% (13/25) and 84.0% (21/25). While ORR were 92.3% (12/13), 75.0% (3/4), 50.0% (1/2), 50.0% (1/2), 100.0% (4/4) and the CR rates were 76.9% (10/13), 25.0% (1/4), 50.0% (1/2), 50.0% (1/2), 0% (0/6) for AITL, PTCL-NOS, ALCL ALK+, ALCL ALK-, and other subtypes, respectively. Median DoCR was 6.1 months (3.45-NA), median PFS was 8.8 months (7.26-10.71), and 6-month PFS rate were 78.2%.

Conclude: This was the first clinical study demonstrated that new combination of CMOP showed promising antitumor activity in TN-PTCL with manageable safety profiles and dose expansion study at RP2D is ongoing.