GEMHDM2014 : Gem-HDM HDT and ASCT for Relapsed/ Refractory Lymphoma

Study Overview
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Brief Summary
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Objective of study: To evaluate the safety and efficacy of infusional gemcitabine prior to HDM (high-dose melphalan) as HDCT (High Dose Chemotherapy) followed by autologous stem cell transplantation in patients with relapsed/refractory lymphoma.

Detailed Description
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High-dose chemotherapy with autologous stem cell transplantation is the current standard of care for patients with chemosensitive relapsed Hodgkin's lymphoma and aggressive non-Hodgkin's lymphoma, and is an established effective therapy for patients with relapsed follicular lymphoma. Disease relapse remains a major problem, occurring in 50% of these patients, particularly in patients with primary refractory disease or other high-risk features. The addition of gemcitabine to single-agent melphalan as a high-dose conditioning regimen presents a promising combination that may lead to improvements in EFS (Event free survival). If this trial gives encouraging results, it may lead to a phase III trial evaluating this treatment strategy. Drug exposure would be AUC (area under curve) and clinical factors would be things like obesity, renal function, disease characteristics. We would be looking at the safety outcomes - i.e. adverse events as a measure of safety and tolerability. The adverse events would be non-hematological toxicities (any) and whether or not it is related to AUC. AUC in relationship to PFS (progression free survival) is also important (we want to know if we need to adjust dose to improve PFS).

Official Title
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Infusional Gemcitabine and High-dose Melphalan (HDM) Conditioning Prior to (ASCT) Autologous Stem Cell Transplantation for Patients With Relapsed/Refractory Lymphoma

Conditions
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Hodgkin's Lymphoma - Relapsed/Refractory, Non-Hodgkin's Lymphoma - Aggressive, Follicular Lymphoma

Intervention / Treatment
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* Drug: Gemcitabine
* Drug: Melphalan
* Other: ASCT


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability to provide written informed consent Age over 18 years Relapsed/refractory lymphoma after at least 1 prior chemotherapy treatment: Hodgkin's lymphoma Aggressive non-Hodgkin's lymphoma Follicular lymphoma Chemosensitive disease at time of transplantation (i.e. partial response or better to salvage chemotherapy) ECOG (Eastern Cooperative Oncology Group) performance 0-2 Adequate organ function: Cardiac: LVEF (left ventricular ejection fraction)>40% Pulmonary: FEV1 (forced expiratory volume at one second) and DLCO (diffusing capacity of lung for carbon monoxide)>60% predicted Renal: creatinine <150 µmol/L unless caused by ureteric obstruction from lymphoma Liver: No evidence of cirrhosis. ALT (Alanine Aminotransferase) and bilirubin <2x upper limit of normal unless caused by biliary tract obstruction from lymphoma Exclusion Criteria: Clinically significant active infection Active secondary central nervous system disease Other serious co-morbid illness that would compromise study participation. Pregnant or lactating females Prior HDCT/ASCT

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Gemcitabine/Melphalan Condition + ASCT<br>Day -1 - IV gemcitabine 1.5-2.5 g/m2 (depending on dose level assigned) administered as a loading bolus of 75 mg/m2, followed by a continuous infusion of 10 mg/m2/min. immediately following gemcitabine - IV melphalan 200 mg/m2 over 5 minutes. Day 0 •Stem cell infusion Patients will be assigned a dose level using the continual reassessment method based on the toxicity data available at the time of their enrollment. The dosing will start at 1.5 g/m2 and will increase by 0.5 mg/m2 at each level to a maximum of 2.5 g/m2. Dose-limiting toxicity is defined as grade 3 mucositis or skin toxicity lasting more than 3 days before downgrading, or any grade 4 non-hematological toxicity. | Drug: Gemcitabine<br>* gemcitabine 1.5 g/m2 INFUSED<br>Drug: Melphalan<br>* 200 mg/m2<br>Other: ASCT<br>* Day 0 - Stem cell infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival of relapsed/refractory lymphoma patients treated with infusional gemcitabine, high dose melphalan (Gem-Mel) and ASCT | The goal is to improve overall 3-year PFS by 15% over what would be expected with standard conditioning regimens. Patients will be stratified into 3 groups according to disease: (a) relapsed/refractory Hodgkins's lymphoma, (b) relapsed/refractory aggressive non-Hodgkin's lymphoma, and (c) relapsed/refractory follicular lymphoma. Grade 3-4 non-hematological toxicity will be defined by the NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) v4. | 3 years | 
| Grade 3-4 Hematological Toxicity | Assessment of Dose-limiting toxicity is defined as grade 3 mucositis or skin toxicity lasting more than 3 days before downgrading, or any grade 4 non-hematological toxicity. | 3 YEARS | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | The goal of this study is to improve overall 3-year PFS rate by 15% with the melphalan gemcitabine conditioning. | 3 Years | 
| Cost Effectiveness | Cost-effectiveness as measured by in-hospital costs of Gemcitabine-Melphalan relative to historical controls treated in Calgary with BEAM or Melphalan+/-TBI (Total Body Irradiation). | 3 Years | 
| Measure of Melphalan pharmacokinetics, AUC (area under curve) | Drug exposure would be AUC (area under curve) . Once the dose of gemcitabine has been established, all subsequent patients will receive a uniform HDCT (high dose chemotherapy) regimen. Patients will undergo blood draws for pharmacokinetic testing at the following time points relative to the end of melphalan infusion: 5 minutes, 30 minutes, 1 hour, 3 hours, 5 hours, 7-10 hours, and 18-23 hours. Samples will be processed at the local pharmacokinetics laboratory in Calgary | 3 Years | 
| Evaluation of relationship between clinical factors and drug exposure in treatment of Gemcitabine/Melphalan with ASCT (autologous stem cell transplantation) | The number of patients with adverse events as a measure of safety and tolerability. | 3 years | 
| Evaluation of relation between drug exposure and non-hematological toxicity and progression free survival | Drug exposure as measured by area under the curve related to number of patients with adverse events (non-hematological toxicity) and progression-free survival | 3 years | 
| Safety Outcomes assessed adverse events as a measure of safety and tolerability | Assess adverse events as a measure of safety and tolerability. The adverse events would be non-hematological toxicities (any) and whether or not it is related to AUC. AUC in relationship to PFS is also important (we want to know if we need to adjust dose to improve PFS). | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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eligible for high-dose therapy and stem cell transplantation