Split-Dose R-CHOP for Older Adults With DLBCL

Study Overview
=================
Brief Summary
-----------------
This study is investigating a new administration schedule of Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone (R-CHOP) chemotherapy for participants with Diffuse Large B-Cell Lymphoma (DLBCL), focusing on an underserved elderly population (aged 75 and up; certain participants 70-74 may be eligible) that is often excluded from clinical trials. Participants can expect to be on study for 2.5 years (treatment for 6 months and 2 years of post treatment follow-up).

Detailed Description
-----------------
This study will test the efficacy of split-dose R-CHOP for the treatment of elderly patients with de novo diagnosis of DLBCL or transformed DLBCL. Split-dose R-CHOP involves giving Cyclophosphamide, Doxorubicin, Vincristine, Prednisone (CHOP) chemotherapy at 14 days' interval with Rituximab given once/month. The safety for every 14-day CHOP administration was studied in a large prospective randomized control trial of patients up to the age of 80 years. In this study, R-CHOP given every 14 days for up to 6 cycles was felt to be the best method of delivery of chemotherapy. Receiving greater than 6 cycles of R-CHOP chemotherapy was not found to be beneficial compared to participants receiving 6 cycles of R-CHOP. Additionally, an interim response adapted approach by combining imaging and MRD testing will be used to identify participants who will receive an abbreviated chemotherapy course if they are both Positron Emission Tomography/Computed Tomography (PET/CT) and Minimum Residual Dose (MRD) negative. In the proposed study, participants will receive a 50% dose reduction of CHOP chemotherapy on Day 1 and Day 15 of each cycle with full dose Rituximab on Day 1 for up to a total of 6 months of chemotherapy. Participants who are MRD and PET/CT negative after 2 months will be placed on an abbreviated regimen with R-CHOP x 4 additional doses with full dose Rituximab and a 50% dose reduction in CHOP chemotherapy. The hypothesis is that this method of administration of R-CHOP will be a safe and effective form of chemotherapy for older patients with DLBCL and will allow older patients to receive curative intent treatment.

Official Title
-----------------
A Phase II Study of Split-Dose R-CHOP in Older Adults With Diffuse Large B-cell Lymphoma

Conditions
-----------------
Diffuse Large B Cell Lymphoma, DLBCL, Cancer

Intervention / Treatment
-----------------
* Drug: Rituximab
* Drug: Cyclophosphamide
* Drug: Doxorubicin
* Drug: Vincristine
* Drug: Prednisone
* Biological: Pegfilgrastim


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Signed and dated informed consent document indicating that the participant (or legally acceptable representative) has been informed of all pertinent aspects of the trial All patients age ≥75 years and participants aged 70-74 years who are determined to be unfit or frail by Cumulative Illness Rating Score-Geriatrics (CIRS-G) scale For participants aged 70-74 years: CIRS-G score with 5-8 comorbid conditions scored 2 or ≥1 comorbidity scored 3-4. CIRS-G score is to be reviewed by the study PI prior to enrollment. Newly diagnosed, untreated, biopsy proven CD20 positive DLBCL (including high grade B-cell lymphoma & T-cell/histiocytic rich large B-cell lymphoma). Participants with discordant bone marrow (i.e. involved by low-grade/indolent NHL) are eligible. Participants with transformed DLBCL from underlying low-grade disease are eligible. Participants with composite DLBCL and concurrent low-grade lymphoma are eligible. Copy of pathology report must be sent to coordinating site to confirm diagnosis for eligibility Participants with prior treatment for low grade NHL with non-anthracycline based regimens are eligible Measurable disease by PET/CT or Bone Marrow (BM) biopsy prior to enrollment Left ventricular ejection fraction ≥50% by resting echocardiography or resting Multi-gated acquisition (MUGA) scan Karnofsky Performance Score ≥50 Ann Arbor Stage II bulky, III, or IV disease Minimum life expectancy greater than 3 months Negative HIV test For participants with hepatitis B virus antigen (HbsAg) or core antibody (HbcAb) seropositivity, participants must have a negative Hep B viral load and an appropriate prophylaxis plan must be in place during chemotherapy therapy treatment. For all participants that have Hep B core antibody positive, they should take entecavir prophylaxis (0.5 mg PO daily) until 1 year from completion of chemotherapy. Hep B viral load should be checked on these participants prior to starting chemotherapy and every 3 months thereafter if initial Hep B viral load is negative (+/- 1 week if chemotherapy cycle is delayed). If Hep B viral load is positive, Hepatology or Identification (ID) referral is recommended, and hepatitis B virus (HBV) viral load should be checked monthly For participants with hepatitis C Ab (HbcAb) positivity, a viral load must be checked and be negative for enrollment Intrathecal chemotherapy for central nervous system prophylaxis only can be given at the discretion of the primary oncologist Exclusion Criteria: History of previous anthracycline exposure Central Nervous System (CNS) or meningeal involvement at diagnosis Creatinine Clearance <25 mL/min by body surface area (BSA)-adjusted Cockroft-Gault Poor hepatic function, defined as total bilirubin concentration greater than 3.0 mg/dL or transaminases over 4 times the maximum normal concentration, unless these abnormalities are felt to be related to the lymphoma. Pulmonary dysfunction defined as >2 L of oxygen required by nasal cannula to maintain peripheral capillary oxygen saturation (SpO2) ≥90% unless felt to be related to underlying lymphoma. Myocardial Infarction within 6 months of enrollment Active, uncontrolled infectious disease Known concurrent bone marrow malignancies (e.g. myelodysplastic syndrome) or poor bone-marrow reserve, defined as neutrophil count less than 1.5×10⁹/L or platelet count less than 100×10⁹/L, unless caused by bone-marrow infiltration with lymphoma History of a second concurrent active malignancy or prior malignancy which required chemotherapy treatment within the preceding 2 years Treatment with any investigational drug within 30 days before the planned first cycle of chemotherapy Unable or unwilling to sign consent

Ages Eligible for Study
-----------------
Minimum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Split Dose R-CHOP<br>Each cycle is 28 days and consists of one A treatment on Day 1 and one B treatment on Day 15 for 6 cycles Day 1 (A part of cycle) Rituximab 375 mg/m2 IV (or biosimilars Ruxience or Truxima) Cyclophosphamide 375 mg/m2 IV Doxorubicin 25 mg/m2 IV Vincristine 1 mg IV Prednisone 50 mg (Days 1-5) PO Pegfilgrastim (supportive care) 6 mg on Day 2 (24 hours after completion of chemotherapy) or filgrastim daily as institutionally indicated (starting 24 hours post completion of chemotherapy), or institutional standard granulocyte stimulating factor. Day 15 (B part of cycle) Cyclophosphamide 375 mg/m2 IV Doxorubicin 25 mg/m2 IV Vincristine 1 mg IV Prednisone 50 mg (Days 15-19) PO Pegfilgrastim (supportive care) 6 mg on Day 16 (24 hours after completion of chemotherapy) or filgrastim daily as institutionally indicated (starting 24 hours post completion of chemotherapy), or institutional standard granulocyte stimulating factor. | Drug: Rituximab<br>* Rituximab is a monoclonal antibody<br>* Other names: Rituxan;Drug: Cyclophosphamide<br>* Chemotherapy drug, alkylating agent<br>* Other names: Cytoxan;Drug: Doxorubicin<br>* Chemotherapy drug, anthracycline antibiotic<br>* Other names: Adriamycin;Drug: Vincristine<br>* Chemotherapy drug, plant alkaloid<br>Drug: Prednisone<br>* Steroid, anti-inflammatory<br>Biological: Pegfilgrastim<br>* Granulocyte stimulating factor, biologic response modifier<br>* Other names: filgrastim;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response Rate (CR) | Simon 2-stage design with complete response (CR) rate at the end of treatment as our primary outcome. 40% is an unacceptable boundary for complete response rate and 60% as an acceptable complete response rate. CR at the end of treatment, will be estimated as the observed proportion and presented with a 95% Wilson confidence interval. | up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | PFS measures survival without relapse/progression or death starting from study enrollment. Relapse or progression of disease and death will be considered as events; subjects who survive without recurrence or progression will be censored at last contact. PFS will be estimated using the Kaplan Meier estimate and presented with graphically with pointwise 95% confidence intervals. | up to 2 years 6 months | 
| Overall Survival (OS) | OS measures time to death starting from study enrollment. Death from any cause will be considered an event; surviving subjects will be censored at time of last follow-up. OS will be estimated using the Kaplan-Meier estimate and presented with graphically with pointwise 95% confidence intervals. Exploratory Cox proportional hazards regression will be used to evaluate the effect of baseline covariates on PFS and OS. | up to 2 years 6 months | 
| Incidence of Treatment Emergent Adverse Events | The incidence of serious adverse events will be reported for all subjects who received at least one dose of the study treatment. The proportion of subjects experiencing a Serious Adverse Event (SAE) will be reported with 95% confidence intervals overall, as well as classified by grade and organ system. Toxicity will be monitored using the formal boundary described in the protocol. | up to 2 years 6 months | 
| Cancer-Specific Geriatric Assessment | Cancer-specific geriatric assessment prior to, during, and after completion of chemotherapy treatments to evaluate for changes in physical function, mental health, cognition, and other relevant geriatric specific outcomes. The geriatric assessment measures will be summarized descriptively at each measurement time-point using appropriate descriptive statistics such as frequencies and percentages with standard errors for categorical variables, mean with standard error or median with quartiles for continuous variables. | up to 2 years 6 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
chemotherapy, cancer, elderly, lymphoma