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

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

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.

Study Overview

• Status: Terminated
• Conditions: Follicular Lymphoma; Hodgkin's Lymphoma - Relapsed/Refractory; Non-Hodgkin's Lymphoma - Aggressive
• Intervention / Treatment: Drug: Gemcitabine; Drug: Melphalan; Other: ASCT

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Actual): 100
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N2
      • Tom Baker Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Ability to provide written informed consent
2. Age over 18 years

3. Relapsed/refractory lymphoma after at least 1 prior chemotherapy treatment:

   1. Hodgkin's lymphoma
   2. Aggressive non-Hodgkin's lymphoma
   3. Follicular lymphoma
4. Chemosensitive disease at time of transplantation (i.e. partial response or better to salvage chemotherapy)
5. ECOG (Eastern Cooperative Oncology Group) performance 0-2

6. Adequate organ function:

   1. Cardiac: LVEF (left ventricular ejection fraction)>40%
   2. Pulmonary: FEV1 (forced expiratory volume at one second) and DLCO (diffusing capacity of lung for carbon monoxide)>60% predicted
   3. Renal: creatinine <150 µmol/L unless caused by ureteric obstruction from lymphoma
   4. 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:

1. Clinically significant active infection
2. Active secondary central nervous system disease
3. Other serious co-morbid illness that would compromise study participation.
4. Pregnant or lactating females
5. Prior HDCT/ASCT

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Gemcitabine/Melphalan Condition + ASCT; 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; gemcitabine 1.5 g/m2 INFUSED; Drug: Melphalan; 200 mg/m2; Other: ASCT; Day 0 - Stem cell infusion

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: AHS Cancer Control Alberta
• Collaborators: Tom Baker Cancer Centre
• Investigators: Principal Investigator: MONA SHAFEY, MD, Tom Baker Cancer Centre

Study record dates

Study Major Dates

• Study Start: April 1, 2015
• Primary Completion (Actual): February 1, 2023
• Study Completion (Actual): February 1, 2023

Study Registration Dates

• First Submitted: October 30, 2014
• First Submitted That Met QC Criteria: November 18, 2014
• First Posted (Estimated): November 20, 2014

Study Record Updates

• Last Update Posted (Actual): July 8, 2024
• Last Update Submitted That Met QC Criteria: July 4, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Keywords: eligible for high-dose therapy and stem cell transplantation
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Melphalan; Gemcitabine
• Other Study ID Numbers: GEMHDM2014

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO