Tailoring Treatment for B Cell Non-hodgkin's Lymphoma Based on PET Scan Results Mid Treatment

Study Overview
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Brief Summary
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The purpose of this study is to assess whether patients who are likely to fail R-CHOP, as predicted by a mid-treatment PET scan, can have an improved outcome if switched to a standard salvage regimen R-ICE (rituximab, ifosfamide, carboplatin, etoposide). Patients who have a negative PET scan after 4 cycles of R-CHOP have an excellent prognosis (>85% chance of cure) and should complete treatment with 6 cycles of standard R-CHOP. Patients who have a positive PET scan after 4 cycles of R-CHOP have a very poor prognosis ( 10% chance of cure) and may have an improved outcome if switched to a non-cross resistant chemotherapy combination R-ICE.

Detailed Description
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This is a phase II trial investigating tailoring first-line therapy for advanced stage diffuse large B-cell NHL (DLBCL) based on a mid-treatment 18F-FDG- positron-emission tomography (PET) scan result. More than half of all patients with DLBCL can be cured with 6-8 cycles of standard R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). Patients who are not cured with R-CHOP have a very poor prognosis. This study will assess whether patients who are likely to fail R-CHOP, as predicted by a mid-treatment PET scan, can have an improved outcome if switched to a standard salvage regimen R-ICE (rituximab, ifosfamide, carboplatin, etoposide). Objectives: To assess the efficacy of tailoring first-line therapy based on a mid- treatment PET scan result for patients with advanced stage DLBCL. To assess the progression-free survival (PFS) in patients with advanced stage DLBCL who have a negative mid-treatment PET scan and receive standard therapy with six cycles of CHOP-R and patients with a positive mid-treatment PET scan who receive four cycles of CHOP-R followed by four cycles of R-ICE chemotherapy. To assess the overall survival (OS) in patients with advanced stage DLBCL who have a negative mid-treatment PET scan and receive standard therapy with six cycles of CHOP-R and patients with a positive mid-treatment PET scan who receive four cycles of CHOP-R followed by four cycles of R-ICE chemotherapy.

Official Title
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Phase II Trial Investigating Tailoring First-Line Therapy For Advanced Stage Diffuse Large B-Cell Non-Hodgkin's Lymphoma Based on Mid-Treatment Positron Emission Tomography (PET) Scan Results

Conditions
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Lymphoma, Non-Hodgkin, Advanced Stage Diffuse Large B-Cell Non-Hodgkin's Lymphoma

Intervention / Treatment
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* Drug: Cyclophosphamide
* Drug: Doxorubicin
* Drug: Vincristine
* Drug: Prednisone
* Drug: Ondansetron
* Drug: Dexamethasone
* Drug: Diphenhydramine
* Drug: Acetaminophen
* Drug: Ifosfamide
* Drug: Mesna (IV)
* Drug: Mesna (oral)
* Drug: Carboplatin
* Drug: Etoposide
* Drug: Rituximab
* Drug: Ondansetron
* Drug: Dexamethasone
* Drug: Diphenhydramine
* Drug: Acetaminophen
* Other: PET Scan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 years of age or older newly diagnosed histologically proven CD-20 positive diffuse large B- cell lymphoma by tissue biopsy, listed under peripheral B-cell neoplasm according to the WHO/REAL classification (diffuse large B-cell lymphoma, mediastinal large B-cell lymphoma, T-cell rich B-cell lymphoma, intravascular large B-cell lymphoma) Advanced stage disease defined as - patients with stage III or stage IV disease; or patients with stage I or stage II disease with one of the following additional criteria: B-symptoms, or disease that is not radio- encompassable within a single involved field, or not a candidate for brief chemotherapy and irradiation, or the presence of bulky disease (any single mass => 10 cm) Previously untreated or treated with up to 3 cycles of standard dose 3- weekly R-CHOP chemotherapy prior to enrollment (i.e. patients may be enrolled prior to initiation of the fourth cycle of R-CHOP chemotherapy) ECOG Performance Status 0,1 or 2 at time of enrollment No evidence of progressive disease while on R-CHOP chemotherapy The patient must sign the consent form prior to registration Exclusion Criteria: Patients with a history of any other lymphoproliferative disorder, including prior history of indolent NHL Patients with a history of prior or concurrent malignancies within 5 years of the current diagnosis, except adequately treated non- melanoma skin cancer, and curatively treated in-situ cancer of the cervix Known HIV infection Known hepatitis B virus infection Pregnancy or lactation. Men and women of childbearing age must be using adequate contraception. Significant renal insufficiency (serum creatinine > 200 mmol/L), unless due to lymphoma Significant hepatic insufficiency (serum total bilirubin > 30 mmol/L), unless due to lymphoma Cardiac contraindication to doxorubicin therapy (e.g. abnormal contractility on echocardiography). If history of cardiac disease, ejection fraction must be within normal limits for age. Neurologic contraindication to vincristine (e.g. peripheral neuropathy) Absolute neutrophil count <1.5 x 109/L (unless due to bone marrow involvement with lymphoma or due to initiation of R-CHOP chemotherapy) Platelet count < 100 x 109/L (unless due to splenomegaly, bone marrow involvement with lymphoma or due to initiation of R-CHOP chemotherapy) Evidence of active systemic infection Any medical condition that in the opinion of the investigator would compromise treatment delivery, add toxicity or impair assessment

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: R-CHOP (Negative Mid-Treatment PET Scan)<br>All participants will receive 4 cycles of standard dose R-CHOP chemotherapy administered at 3-weekly intervals. Non-progressing participants will undergo a mid-treatment PET scan along with routine restaging investigations after 4 cycles of R-CHOP. Patients with a negative mid-treatment PET scan (no evidence of abnormal 18F-FDG uptake) will complete therapy with two additional cycles of R-CHOP for a total of 6 cycles of chemotherapy. Patients with a mid-treatment PET scan interpreted to be indeterminate or equivocal will be recorded as such, but should be considered negative for the purpose of treatment planning and should not prompt a change in therapy. | Drug: Cyclophosphamide<br>* Dose: 750 mg/m^2 Administration: IV infusion day 1 over 20-60 minutes Schedule: Cycle 1, 2, 3, 4, 5*, 6* (Week 1, 4, 7, 10, 14, 17) * Cycles 5 and 6 of R-CHOP will be administered only to patients with a negative mid-treatment PET scan<br>* Other names: Cytoxan®, Neosar®;Drug: Doxorubicin<br>* Dose: 50 mg/m^2 Administration: IV Push day 1 Schedule: Cycle 1, 2, 3, 4, 5*, 6* (Week 1, 4, 7, 10, 14, 17) * Cycles 5 and 6 of R-CHOP will be administered only to patients with a negative mid-treatment PET scan<br>* Other names: Adriamycin ®, Rubex®;Drug: Vincristine<br>* Dose: 1.4 mg/m^2 Administration: IV Push day 1 Schedule: Cycle 1, 2, 3, 4, 5*, 6* (Week 1, 4, 7, 10, 14, 17) * Cycles 5 and 6 of R-CHOP will be administered only to patients with a negative mid-treatment PET scan<br>* Other names: Oncovin ®, Vincasar Pfs ®, Vincristine Sulfate, LCR, VCR;Drug: Prednisone<br>* Dose: 45 mg/m^2 Administration: IV infusion day 1 (or day 2) over 90 minutes-8 hours Schedule: Cycle 1, 2, 3, 4, 5*, 6* (Week 1, 4, 7, 10, 14, 17) * Cycles 5 and 6 of R-CHOP will be administered only to patients with a negative mid-treatment PET scan<br>* Other names: Sterapred®, Sterapred® DS, Prednisone Intensol;Drug: Ondansetron<br>* Premedication for R-CHOP Dose: 8 mg Route: PO Schedule: 15 min pre-CHOP chemotherapy<br>* Other names: Zofran®, Zofran® ODT, Zuplenz®;Drug: Dexamethasone<br>* Premedication for R-CHOP Dose: 12 mg Route: PO Schedule: 15 min pre-CHOP chemotherapy<br>* Other names: Decadron®, Dexamethasone Intensol®, Dexpak® Taperpak®;Drug: Diphenhydramine<br>* Premedication for R-CHOP Dose: 50 mg Route: PO Schedule: Prior to rituximab and then q 4h during rituximab infusion<br>* Other names: Aler-Dryl®, Benadryl®, Nytol®, Diphenhist®;Drug: Acetaminophen<br>* Premedication for R-CHOP Dose: 650 mg Route: PO Schedule: Prior to rituximab and then q 4h during rituximab infusion<br>* Other names: Tylenol®;Other: PET Scan<br>* Investigations: 18F-FDG-PET scan Timing: After 4 cycles of R-CHOP (days 21-28) and after 4 cycles of R-ICE (days 28-35)<br>* Other names: Positron emission tomography (PET) scan;|
| Active Comparator: R-ICE (Positive Mid-Treatment PET Scan<br>All participants will receive 4 cycles of standard dose R-CHOP chemotherapy administered at 3-weekly intervals. Non-progressing participants will undergo a mid-treatment PET scan along with routine restaging investigations after 4 cycles of R-CHOP. Patients with a mid-treatment PET scan (abnormal 18F-FDG uptake) will be switched to R-ICE chemotherapy and receive 4 cycles of R-ICE for a total of 8 cycles of chemotherapy. Following completion of R-ICE chemotherapy, patients will undergo a post-treatment PET scan along with routine restaging investigations. The post-treatment PET scan will be performed between days 28 and 35 following the final cycle of R-ICE. Patients with a negative post-treatment PET scan will undergo no further therapy. Patients with a positive post-treatment PET scan corresponding to persistent abnormalities on CT scan will be considered for radiation therapy to PET positive sites. | Drug: Cyclophosphamide<br>* Dose: 750 mg/m^2 Administration: IV infusion day 1 over 20-60 minutes Schedule: Cycle 1, 2, 3, 4, 5*, 6* (Week 1, 4, 7, 10, 14, 17) * Cycles 5 and 6 of R-CHOP will be administered only to patients with a negative mid-treatment PET scan<br>* Other names: Cytoxan®, Neosar®;Drug: Doxorubicin<br>* Dose: 50 mg/m^2 Administration: IV Push day 1 Schedule: Cycle 1, 2, 3, 4, 5*, 6* (Week 1, 4, 7, 10, 14, 17) * Cycles 5 and 6 of R-CHOP will be administered only to patients with a negative mid-treatment PET scan<br>* Other names: Adriamycin ®, Rubex®;Drug: Vincristine<br>* Dose: 1.4 mg/m^2 Administration: IV Push day 1 Schedule: Cycle 1, 2, 3, 4, 5*, 6* (Week 1, 4, 7, 10, 14, 17) * Cycles 5 and 6 of R-CHOP will be administered only to patients with a negative mid-treatment PET scan<br>* Other names: Oncovin ®, Vincasar Pfs ®, Vincristine Sulfate, LCR, VCR;Drug: Prednisone<br>* Dose: 45 mg/m^2 Administration: IV infusion day 1 (or day 2) over 90 minutes-8 hours Schedule: Cycle 1, 2, 3, 4, 5*, 6* (Week 1, 4, 7, 10, 14, 17) * Cycles 5 and 6 of R-CHOP will be administered only to patients with a negative mid-treatment PET scan<br>* Other names: Sterapred®, Sterapred® DS, Prednisone Intensol;Drug: Ondansetron<br>* Premedication for R-CHOP Dose: 8 mg Route: PO Schedule: 15 min pre-CHOP chemotherapy<br>* Other names: Zofran®, Zofran® ODT, Zuplenz®;Drug: Dexamethasone<br>* Premedication for R-CHOP Dose: 12 mg Route: PO Schedule: 15 min pre-CHOP chemotherapy<br>* Other names: Decadron®, Dexamethasone Intensol®, Dexpak® Taperpak®;Drug: Diphenhydramine<br>* Premedication for R-CHOP Dose: 50 mg Route: PO Schedule: Prior to rituximab and then q 4h during rituximab infusion<br>* Other names: Aler-Dryl®, Benadryl®, Nytol®, Diphenhist®;Drug: Acetaminophen<br>* Premedication for R-CHOP Dose: 650 mg Route: PO Schedule: Prior to rituximab and then q 4h during rituximab infusion<br>* Other names: Tylenol®;Drug: Ifosfamide<br>* R-ICE Chemotherapy Schedule (cycles repeated every 3 weeks) Dose: 5000 mg/m^2 (total dose per cycle) Administration: In 3 equally divided doses IV infusion days 1,2,3, over 2 hours Schedule: Cycle 1, 2, 3, 4 (Week 14, 16, 20, 23)<br>* Other names: Ifex®, Isophosphamide;Drug: Mesna (IV)<br>* R-ICE Chemotherapy Schedule (cycles repeated every 3 weeks) Dose: 5000 mg/m^2 (total dose per cycle) Administration: In 3 equally divided doses IV infusion days 1,2,3 (with ifosfamide) over 2 hours Schedule: Cycle 1, 2, 3, 4 (Week 14, 16, 20, 23)<br>* Other names: Mesnex®, Sodium 2-mercaptoethanesulfonate;Drug: Mesna (oral)<br>* R-ICE Chemotherapy Schedule (cycles repeated every 3 weeks) Dose: 2 g Administration: PO 2h and 4h after ifosfamide infusion on days 1,2,3 Schedule: Cycle 1, 2, 3, 4 (Week 14, 16, 20, 23)<br>* Other names: Mesnex®, Sodium 2-mercaptoethanesulfonate;Drug: Carboplatin<br>* R-ICE Chemotherapy Schedule (cycles repeated every 3 weeks) Dose: 5 x (25+CrCl*) (maximum dose 800 mg) Administration: IV infusion day 1 over 1 hour Schedule: Cycle 1, 2, 3, 4 (Week 14, 16, 20, 23) *Carboplatin is dose via the Calvert formula with an AUC of 5, maximum dose 800 mg per cycle. Estimate Creatinine Clearance (CrCl)<br>* Other names: CBDCA;Drug: Etoposide<br>* R-ICE Chemotherapy Schedule (cycles repeated every 3 weeks) Dose: 100 mg/m^2 Administration: IV infusion day 1,2,3 over 30 minutes Schedule: Cycle 1, 2, 3, 4 (Week 14, 16, 20, 23)<br>* Other names: Etopophos®, VP-16;Drug: Rituximab<br>* R-ICE Chemotherapy Schedule (cycles repeated every 3 weeks) Dose: 375 mg/m^2 Administration: IV infusion day 1 (or day 2 or day 3) over 90 minutes-8 hours Schedule: Cycle 1, 2, 3, 4 (Week 14, 16, 20, 23)<br>* Other names: Rituxan®;Drug: Ondansetron<br>* Premedication for R-ICE Dose: 8 mg Route: PO Schedule: 15 min pre-chemotherapy daily<br>* Other names: Zofran®, Zofran® ODT, Zuplenz®;Drug: Dexamethasone<br>* Premedication for R-ICE Dose: 8 mg Route: PO Schedule: 15 min pre-chemotherapy daily<br>* Other names: Decadron®, Dexamethasone Intensol®, Dexpak® Taperpak®;Drug: Diphenhydramine<br>* Premedication for R-ICE Dose: 50 mg Route: PO Schedule: Prior to rituximab and then q 4h during rituximab infusion<br>* Other names: Aler-Dryl®, Benadryl®, Nytol®, Diphenhist®;Drug: Acetaminophen<br>* Premedication for R-ICE Dose: 650 mg Route: PO Schedule: Prior to rituximab and then q 4h during rituximab infusion<br>* Other names: Tylenol®;Other: PET Scan<br>* Investigations: 18F-FDG-PET scan Timing: After 4 cycles of R-CHOP (days 21-28) and after 4 cycles of R-ICE (days 28-35)<br>* Other names: Positron emission tomography (PET) scan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) in participants with advanced stage DLBCL | Progression-free survival (PFS) in participants with advanced stage DLBCL who have a negative mid-treatment PET scan and receive standard therapy with six cycles of CHOP-R and patients with a positive mid-treatment PET scan who receive four cycles of CHOP-R followed by four cycles of R-ICE chemotherapy. Progression-free survival is defined as the duration of time from diagnosis to time of disease progression or death from any cause. Living patients who have remained free of progression will have their PFS censored on the date last known alive. | Estimated two years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) in participants with advanced stage DLBCL | Overall survival (OS) in participants with advanced stage DLBCL who have a negative mid-treatment PET scan and receive standard therapy with six cycles of CHOP-R and patients with a positive mid-treatment PET scan who receive four cycles of CHOP-R followed by four cycles of R-ICE chemotherapy. Overall survival will be defined as the time from diagnosis to the date of death. If the participant is lost to follow-up, survival will be censored on the last date the participant was known to be alive. | Several years | 
| The safety of R-ICE therapy in first-line therapy of DLBCL following four cycles of R-CHOP as assessed using the NCI Common Terminology Criteria for Adverse Events Version 3.0 |  | Six months | 
| Investigate clinical and biologic markers that characterize participant heterogeneity and may serve as predictors of response to therapy and overall outcome. | A central pathology review of original diagnostic biopsies will be performed by pathologists at the Coordinating Center to ensure appropriate lymphoma subclassification. This centralized review is not required prior to enrollment, provided the patients biopsy has been carefully reviewed by local pathologists and determined to be DLBCL. Correlative studies of biologic markers will be performed on cases with adequately preserved tissue to explore the biologic heterogeneity between patients and to investigate determinants of response to therapy. | 1 year | 
| Efficacy of tailoring first-line therapy bases on a mid-treatment PET scan result for patients with advanced stage DLBCL | All patients will have their BEST RESPONSE on study classified as outlined below. For patients with more than six measurable lesions the six most distinctly measurable at diagnosis should be chosen for response assessment by CT scanning. If available, lesions from both above and below the diaphragm should be chosen, at least two from each region. | Four to six months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NON-HODGKIN'S LYMPHOMA, POSITRON EMISSION TOMOGRAPHY, PET, DLBCL, R-CHOP, R-ICE