Clinical trial NCT05257018: R-CDOP Combined With Intrathecal Methotrexate for DLBCL Patients With High-risk of CNS Relapse
Official title: A Phase II Study of R-CDOP Combined With Intrathecal Methotrexate for Diffuse Large B-cell Lymphoma Patients With High-risk of Central Nervous System Relapse
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Diffuse Large B-cell Lymphoma
Keywords: Chemo-naive Diffuse Large B-cell Lymphoma
Doxorubicin Hydrochloride Liposome Injection
Methotrexate
Central Nervous System Relapsed
R-CDOP
Objective Response Rate
Progression Free Survival
2-year CNS relapse rate
Lead sponsor: Fudan University
Sponsor class: OTHER
First posted: 2022-02-25
Enrollment: 83
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a double-center, single-arm, phase 2 study to evaluate the efficacy and safety of R-CDOP regimen combined with intrathecal methotrexate in chemo-naive diffuse large B-cell lymphoma patients with high-risk of CNS relapse.

Detailed description: Diffuse large B-cell lymphoma is the most common subtype of non-Hodgkin's lymphoma, accounting for 31% of all non-Hodgkin's lymphomas. At present, the standard treatment is R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) Regimen. In DLBCL, central nervous system recurrence is rare, but once it occurs, it is often fatal. The prognosis of patients with central recurrence of DLBCL is very poor, and the median survival time is only 3.5-7 months.The CNS relapse rate of the R-CHOP regimen combined with MTX (methotrexate) intrathecal in high CNS-IPI DLBCL patients is approximately 12%.

This study was a phase II, prospective, single arm，double-center study, which requires a total of 83 DLBCL patients with high-risk of CNS relapse.

Patients will receive a total of 6-8 cycles of R-CDOP regimen, repeated every 3 weeks. Intrathecal MTX will be administered after the 1st-5th cycle of chemotherapy. All the patients will receive a mid-treatment PET scan after 4 cycles of chemotherapy. Patient achieves CR (complete response) after 4 cycles will continue to receive another 2 cycles of treatment. For those who achieve PR, another 4 cycles of chemotherapy will given.

Eligibility criteria: Inclusion Criteria:

1. Age range from 18 to 75 years;
2. ECOG performance status: 0-2;
3. Histopathologically confirmed untreated diffuse large B-cell lymphoma (cell origin can be distinguished according to Hans algorithm) , And fulfilled the following criteria for high-risk CNS recurrence:

   1. CNS-IPI 4-6;
   2. The lymphoma involved testis, breast (excluding unilateral breast and less than 5 cm mass), adrenal gland, kidney, paranasal sinus, paravertebral, and bone marrow and other sites;
   3. PCLBCL-leg;
4. Subjects have at least one measurable lesion: the long axis of the lymph node shall be\>1.5 cm, the long axis of the extranodal lesions shall be\>1.0 cm;
5. Bone marrow hematopoiesis was essentially normal: WBC≥3.5 ×10\^9/L, ANC≥1.5×10\^9/L, PLT≥80×10\^9/L, Hb≥90 g/L. Abnormal peripheral blood indices, as a result of lymphoma invading the bone marrow or spleen, permitted enrollment at the discretion of the investigator;
6. Liver function: total bilirubin, ALT, AST \< 1.5×UNL (upper limit of normal);
7. Renal function: Cr \< 1.5×UNL and creatinine clearance≥30 ml/min;
8. Echocardiography or nuclide cardiac function testing with LVEF≥50%;
9. Patients in the reproductive period agreed to appropriate contraception. Women in the reproductive period had a negative serum pregnancy test within 2 weeks before enrollment;
10. Consent to provide pathological tissue specimens (wax blocks within half a year or 20 slides for paraffin tissue sections);
11. Life expectancy≥3 months;
12. Signed informed consent;

Exclusion Criteria:

1. Patients with a known history of severe allergy to humanized or murine mAbs, or any contraindication to R-CDOP, intrathecal MTX;
2. Patients with evidence of CNS involvement (baseline cerebrospinal fluid, imaging, symptoms);
3. Special types of diffuse large B-cell lymphoma patients who are not suitable for induction therapy with R-CDOP, such as PMBCL, double-hit large B-cell lymphoma, etc;
4. Clinically significant cardiac conditions, including severe cardiac insufficiency: New York Heart Association (NYHA) cardiac insufficiency class IV, unstable angina, acute myocardial infarction within 6 months prior to screening, congestive heart failure, and Q-Tc interval greater than 500 ms;
5. Those who had a second degree or greater operation within three weeks before treatment;
6. Diagnosed with a malignancy other than lymphoma or under treatment, with the following exceptions:

   1. Had received treatment with curative intent and had not developed malignancy with known active disease ≥ 5 years prior to enrollment;
   2. Basal cell carcinoma of the skin (other than melanoma) that has been adequately treated with no evidence of disease;
   3. Carcinoma in situ of the cervix that has been adequately treated with no evidence of disease;
7. Had significant coagulation abnormalities;
8. Any previous antilymphoma therapy other than short-term corticosteroids (up to 10 days);
9. Those with severe active infection;
10. Other serious, uncontrolled concomitant conditions that may affect protocol adherence or interfere with interpretation of results include uncontrolled diabetes mellitus, or pulmonary disease (interstitial pneumonia, obstructive pulmonary disease, and a history of symptomatic bronchospasm), hypertension, and others;
11. HBV (HBsAg positive and HBV-DNA ≥ 104 IU / ml), HCV (HCV antibody positive and HCV-RNA measurable); And subjects with other acquired, congenital immunodeficiency diseases, including but not limited to those with HIV infection;
12. Pregnant or lactating women;

Primary outcomes:
measure: 2-year central nervous system relapse rate
timeFrame: up to 6 years after the start of the study
measure: Concentration of doxorubicin in cerebrospinal fluid after using doxorubicin hydrochloride liposome injection
timeFrame: up to 4 years after the start of the study
Secondary outcomes:
measure: Objective response rate (ORR)
timeFrame: 2 years after enrollment of final patient
measure: 2-year progression-free survival (PFS) rate
timeFrame: 2 years after enrollment of final patient
measure: 2-year event-free survival (EFS) rate
timeFrame: 2 years after enrollment of final patient
measure: Overall Survival (OS)
timeFrame: 2 years after enrollment of final patient
measure: Adverse events
timeFrame: Since the signing of informed consent forms to 30 days after the last cycle
measure: Cmax（maximum concentration）
timeFrame: Time from zero to Tmax
measure: Tmax（maximum time）
timeFrame: Time from zero to Cmax
measure: T1/2（drug half time）
timeFrame: The time it takes for blood concentration levels to drop by half
measure: AUC（0-∞）（area under the curve）
timeFrame: Time from zero to ∞
measure: AUC （0-t）（area under the curve from time zero to the last observation time
timeFrame: Time from zero to the last observation time
Other outcomes:
Locations:
city: Shanghai
country: China
facility: Dongmei Ji
state: Shanghai
city: Ürümqi
country: China
facility: Cancer Hospital affilicaited to Xinjiang Medical University
state: Xinjiang
Study officials:
affiliation: Fudan University
name: Dongmei Ji, doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: Fudan University
name: Junning Cao, Doctor
role: PRINCIPAL_INVESTIGATOR
References: