Interferon and GM-CSF Compared With Imatinib Mesylate and Vaccine Therapy in Patients With Chronic Phase CML on a TKI

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Tyrosine kinase inhibitors may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Interferon alfa may interfere with the growth of cancer cells. GM-CSF may help cells that are involved in the body's immune response work better. Vaccines made from a person's cancer cells may help the body build an effective immune response to kill cancer cells. PURPOSE: This randomized phase II trial is studying tyrosine kinase inhibitors, interferon alfa, and GM-CSF to see how well they work compared to tyrosine kinase inhibitors and vaccine therapy in treating patients with chronic phase chronic myelogenous leukemia.

Detailed Description
-----------------
OBJECTIVES: Primary Compare clinical response, in terms of 1-year progression-free survival and rate of molecular complete remission, in patients with Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+ CML) in chronic phase who have achieved a complete cytogenetic remission to single-agent tyrosine kinase inhibitor treated with interferon alfa and sargramostim (GM-CSF) vs tyrosine kinase inhibitor and GM-K562 cell vaccine. Secondary Compare time to Ph-negativity by polymerase chain reaction after randomization. Compare disease-free survival and percent molecular complete remissions. Determine the toxicity of these treatment regimens in these patients. OUTLINE: This is a multicenter, randomized, crossover, study. Patients are randomized to 1 of 2 treatment arms. The study will be modified based on the results of the planned interim analysis. Individual Study Arms will continue to accrue and treat as indicated by the analysis. The study in its current format will continue should the planned interim analysis indicate both Study Arms remain viable as effective treatments. All patients continue to receive their standard dose of tyrosine kinase inhibitor in addition to 1 of the following treatment arms: Arm I : Patients receive interferon alfa subcutaneously (SC) and GM-CSF SC once daily for 6 months. Patients who achieve a molecular complete remission (CR) (defined as BCR-ABL-negative disease confirmed by 2 PCR assays separated by 1 month) at the end of the 6-month period, discontinue study therapy and are monitored for disease recurrence by blood tests every 4 weeks. Patients who do not achieve a molecular CR (defined as BCR-ABL-positive disease) after completion of the initial 6 months of therapy, receive an additional 6 months of therapy as above. Patients who achieve BCR-ABL-negative disease during the additional 6 months of therapy, discontinue study therapy and are monitored for disease recurrence by blood tests every 4 weeks. Patients who remain BCR-ABL-positive by PCR after an additional 6 months of therapy, are eligible to cross over to arm II. If at any time after stopping study therapy blood tests show disease recurrence, patients restart tyrosine kinase inhibitor and are eligible to cross over to arm II. Patients are also eligible to cross over to arm II in the presence of unacceptable toxicity. Arm II: Patients receive GM-K562 cell vaccine intradermally once every 3 weeks for a minimum of 6 months. Patients with BCR-ABL-negative disease at the end of the 6-month period discontinue study therapy and are monitored for disease recurrence by blood tests every 4 weeks. Patients with BCR-ABL-positive disease after the completion of the initial 6 months of therapy, receive an additional 6 months of therapy as above. Patients who achieve BCR-ABL-negative disease during the additional 6 months of therapy, discontinue study therapy and are monitored every 4 weeks for disease recurrence. Patients who remain BCR-ABL-positive after the additional 6 months of therapy, are eligible to cross over to arm I. If at any time after stopping study therapy blood tests show disease recurrence, patients restart tyrosine kinase inhibitor and are eligible to cross over to arm I. Patients are also eligible to cross over to arm I in the presence of unacceptable toxicity. After completion of study therapy, patients are followed periodically for up to 1 year. As of May 2014, Study Arm B is not available to newly accrued and enrolled subjects based on the interim analysis directing all new subjects to the combination of Interferon + GM-CSF. PROJECTED ACCRUAL: A total of 56 patients will be accrued for this study.

Official Title
-----------------
A Randomized Phase II Trial of Interferon + GM-CSF Versus K562/GM-CSF Vaccination in CML Patients Achieving a Complete Cytogenetic Response to Frontline Tyrosine Kinase Inhibitor Therapy

Conditions
-----------------
Leukemia

Intervention / Treatment
-----------------
* Biological: GM-K562 cell vaccine
* Biological: Interferon alfa
* Biological: Sargramostim


Participation Criteria
=================
Eligibility Criteria
-----------------
DISEASE CHARACTERISTICS: Diagnosis of chronic myelogenous leukemia (CML) in chronic phase based on cytogenetic detection of the Philadelphia chromosome and/or detection of the BCR-ABL rearrangement by any of the following molecular methods: Recombinant DNA analysis of the BCR-ABL fusion gene Fluorescence in situ hybridization (FISH) Polymerase chain reaction detection of the BCR-ABL hybrid mRNA Documentation of complete cytogenetic response by conventional cytogenetic or FISH analysis while on a stable dose of tyrosine kinase inhibitor No other phase of CML PATIENT CHARACTERISTICS: ECG performance status 0-2 Life expectancy > 24 months Not pregnant Negative pregnancy test Fertile patients must use effective contraception Creatinine ≤ 2.0 mg/dL Bilirubin ≤ 2.0 times upper limit of normal (ULN) AST and ALT ≤ 2.5 times ULN No other malignancy within the past 5 years except in situ cervical carcinoma or adequately treated nonmelanoma skin cancer No other disease requiring long-term corticosteroids or immunosuppressants PRIOR CONCURRENT THERAPY: At least 28 days since prior investigational agents No prior bone marrow transplant or other transplant No concurrent immunosuppressants (e.g., steroids, cyclosporine, azathioprine, mycophenolate mofetil, sirolimus, or tacrolimus) No concurrent hydroxyurea, busulfan, or cytoreductive agents (other than frontline TKI) No other concurrent anticancer agents or therapies

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 120 Years

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

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

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

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Participants were randomly assigned to Arm A or Arm B and received up to twelve months of protocol therapy. If at any point a participant progressed, relapsed, or had unacceptable toxicity, they could cross over to the other arm. Participants could only cross over once.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>Patients will receive injections of interferon alfa and sargramostim once a day for 6 months. Some patients may receive treatment for up to 1 year. After 1 year, some patients may receive treatment as in arm II. | Biological: Interferon alfa<br>* Given by injection<br>Biological: Sargramostim<br>* Given by injection<br>* Other names: GM-CSF;|
| Experimental: Arm B<br>Patients will receive an injection of GM-K562 cell vaccine every 3 weeks for at least 6 months. Some patients may receive treatment for up to 1 year. After 1 year, some patients may receive treatment as in arm I. NOTE: Study Arm B is not available to newly accrued and enrolled subjects based on the interim analysis directing all new subjects to the combination of Interferon + sargramostim (Arm A). | Biological: GM-K562 cell vaccine<br>* Given by injection<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Number of patients alive and without disease progression or relapse | 1 year after treatment has been stopped | 
| Complete Remission Rate | Percentage of patients who achieved molecular remission as defined by polymerase chain reaction negativity. | Up to 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Complete Molecular Remission | Number of months from randomization to molecular remission as defined by polymerase chain reaction negativity. | Up to 27 months | 
| Disease-free Survival | Median number of days to progression of disease in participants who stopped all treatment as directed by the protocol. | Up to 8 years | 
| Early Discontinuation | Number of participants unable to complete protocol-specified treatment due to toxicity. | 1 year | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Philadelphia chromosome positive chronic myelogenous leukemia, chronic phase chronic myelogenous leukemia