Cancer, Diffuse Large B Cell Lymphoma, DLBCL
Conditions
Keywords
chemotherapy, cancer, elderly, lymphoma
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.
Interventions
DRUGRituximab
Rituximab is a monoclonal antibody
DRUGCyclophosphamide
Chemotherapy drug, alkylating agent
DRUGDoxorubicin
Chemotherapy drug, anthracycline antibiotic
DRUGVincristine
Chemotherapy drug, plant alkaloid
DRUGPrednisone
Steroid, anti-inflammatory
BIOLOGICALPegfilgrastim
Granulocyte stimulating factor, biologic response modifier
Sponsors
University of Wisconsin, Madison
Medical College of Wisconsin
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
70 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Complete Response Rate (CR) | up to 6 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | up to 2 years 6 months | 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. |
| Overall Survival (OS) | up to 2 years 6 months | 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. |
| Incidence of Treatment Emergent Serious Adverse Events | up 6 months | 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. Toxicity will be monitored using the formal boundary described in the protocol. |
| Summary of Treatment Emergent Serious Adverse Events by Grade and Organ System | up 6 months | The incidence of serious adverse events will be reported for all subjects who received at least one dose of the study treatment. |
| Cancer-Specific Geriatric Assessment | up to 2 years 6 months | 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. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORChristopher Fletcher, MD
University of Wisconsin, Madison
STUDY_CHAIRNirav Shah, MD, MS
Medical College of Wisconsin Clinical Cancer Center
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Customized 70-79 years | 13 Participants |
| Age, Customized 80-89 years | 14 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 26 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 27 Participants |
| Region of Enrollment United States | 27 participants |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 7 / 27 |
| other Total, other adverse events | 27 / 27 |
| serious Total, serious adverse events | 9 / 26 |
Outcome results
None listed