Phase 1-2 of a CpG-Activated Whole Cell Vaccine Followed by Autologous Immunotransplant for MCL

Study Overview
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Brief Summary
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Mantle cell lymphoma (MCL) is a sub-type of non-Hodgkin's lymphoma (NHL) which is generally considered incurable with current therapy. Participants will receive an autologous vaccine against their individual lymphoma after undergoing stem cell transplantation. This vaccination may prolong the time which patients will stay in remission from their disease.

Detailed Description
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Study treatment is a complex set of steps of research procedures and regular medical care. By using a participant's cancer cells as an immungen, the study hopes to improve freedom from molecular residual disease (MRD). PRIMARY OBJECTIVE Freedom from molecular residual disease at 1-year post-autologous transplant. SECONDARY OBJECTIVE Time To Clinical Progression (TTP) This study has 2 research agents, PF-03152676 and CpG-MCL Vaccine. PF-03152676 is a synthetic DNA molecule, 24 nucleotides in length with a nuclease-resistant phosphorothioate backbone. It is an immunostimulatory, single-stranded oligodeoxynucleotide (oligo-DNA) containing unmethylated cytosine and guanine (CpG) motifs and synthesized with a nuclease-resistant phosphorothioate backbone. PF-03512676 acts as an agonist of human Toll-like receptor 9, leading to activation of antigen-presenting cells and a cascade of anti-tumor immune reactions. CpG-MCL Vaccine is the primary study agent. It is prepared by dissociating a participant's harvested tumor cells into a single-cell suspension, and culturing them with PF-03152676 for 72 hours at 37 degrees C, 5% CO2 to allow for up-regulation of antigen-presenting and co-stimulatory molecules, then irradiated to 200 Gy to destroy any remaining cancer propagating ability. The study procedure is summarized as 12 steps, listed below. Step 1. Undergo excisional tumor biopsy or apheresis to obtain tumor cells, which will be used to generate the CpG-MCL vaccine . Step 2. Receive standard induction chemotherapy (regular medical care). Step 3. Once in remission, receive 3 vaccinations of CpG-MCL Vaccine over 3 weeks. With each CpG-MCL vaccination, a concurrent subcutaneous injection of PF-3512676 is administered as an adjuvant. Step 4. About 4 weeks later, receive rituximab 375 mg/m² to minimize any residual tumor. Step 5. Apheresis procedure to harvest the CpG-MCL Vaccine-primed T-cells. Each collection is  1 x 10e10 CD3+ T-cells. Step 6. High-dose cytoxan and filgrastim to mobilize peripheral blood progenitor cell (PBPC). Step 7. Undergo separate apheresis procedure to harvest PBPC). Step 8. Receive myeloablative chemotherapy (regular medical care). Step 9. Receive PBPC infusion (also known as autologous hematopoietic cell transplant, AHCT). Step 10. Within 3 days of AHCT (but typically 1 day), receive infusion of CpG-MCL Vaccine-primed T-cells, followed within 1 hour by a with 4th vaccination with CpG-MCL Vaccine (1st booster vaccination). Step 11. After hematopoietic recovery, receive 5th vaccination with CpG-MCl (2nd booster vaccination). Step 12. Monitor participants for general health and disease status through at least 3 years.

Official Title
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Phase 1-2 Study of a CpG-Activated Whole Cell Vaccine Followed by Autologous Immunotransplant for Mantle Cell Lymphoma

Conditions
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Lymphoma, Mantle-Cell

Intervention / Treatment
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* Biological: CpG-MCL vaccine
* Biological: PF-3512676
* Procedure: Vaccine-primed T-cells
* Procedure: Autologous hematopoietic stem cell transplant (HSCT)
* Drug: Rituximab
* Drug: Standard induction chemotherapy
* Drug: Cyclophosphamide
* Drug: Filgrastim


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA Newly-diagnosed with mantle cell lymphoma (MCL) with accessible disease site for excisional biopsy, OR have sufficient peripheral blood tumor to leukapherese ≥ 1.5 x 10e9 lymphoma cells in a single session Medically appropriate by standard clinical criteria to receive rituximab and standard induction chemotherapy and high-dose chemotherapy with autologous hematopoietic cell transplant (AHCT) HIV-negative Eastern Cooperative Oncology Group (ECOG) Performance Status, OR Karnofsky performance scale 50 to 100% Capable of providing informed consent EXCLUSION CRITERIA Currently receiving immunosuppressive medications Severe psychological or medical illness Pregnant or lactating Unable to safely complete the study, at the discretion of the principal investigator

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 70 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: CpG-MCL Vaccine<br>An autologous anti-tumor vaccine. | Biological: CpG-MCL vaccine<br>* CpG-MCL vaccine is a vaccine prepared by co-culturing cells from the participant's mantle cell lymphoma suspension with 3 mcg/mL PF-3512676, then irradiated to 200 Gy. 1 x 10e8 CpG-MCL cells will be given as a subcutaneous injection.<br>* Other names: Cytosine-Guanosine repeats (CpG)-mantle cell lymphoma (CpG-MCL vaccine);Biological: PF-3512676<br>* PF-03152676 is a synthetic immunostimulatory, single-stranded oligodeoxynucleotide (oligo-DNA) moledule containing unmethylated cytosine and guanine (CpG) motifs. PF-03512676 acts as an agonist of human Toll-like receptor 9, leading to activation of antigen-presenting cells and a cascade of antitumor immune reactions.<br>* Other names: CPG-7909;Procedure: Vaccine-primed T-cells<br>* Vaccine primed T-cells are the post-vaccination leukapheresis harvest of peripheral blood mononuclear cells. Each collection is approx 1 x 10e10 CD3+ T-cells.<br>Procedure: Autologous hematopoietic stem cell transplant (HSCT)<br>* Regular medical procedure<br>* Other names: Autologous peripheral blood stem cell (PBSC) transplant;Drug: Rituximab<br>* 375 mg/m² by infusion<br>* Other names: hera;Drug: Standard induction chemotherapy<br>* Patient-specific, regular medical care treatment as determined by treating oncologist<br>Drug: Cyclophosphamide<br>* Regular medical care treatment to mobilize peripheral blood progenitor cell (PBPC)<br>* Other names: CPM;Drug: Filgrastim<br>* Regular medical care treatment to mobilize peripheral blood progenitor cell (PBPC)<br>* Other names: Neupogen;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Freedom From Molecular Residual Disease (MRD) Post-autologous Stem Cell Transplant (ASCT) | Molecular residual disease (MRD) is defined as detection in blood samples by the ClonoSEQ test of the (11;14) (q13;q32) gene translocation. It is considered positive if a tumor-specific VDJ sequence is detected in the peripheral blood cells by Ig-HTS at a frequency of greater or equal to 1 molecule per 10,000 input leukocyte equivalents of DNA within 1 year post-autologous stem cell transplant (ASCT). The outcome will be reported as number and percent of participants that maintain MRD-negative status (ie, 1-year freedom from MRD). This outcome is reported as a number without dispersion. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time-to-progression (TTP) | Time-to-progression (TTP) is measured from the time of autologous stem cell transplantation (ASCT) until the cancer progresses or relapses. Progression is assessed based on CT imaging per the Cheson Criteria (2008). Progression per the Cheson Criteria is defined as having occurred when the sum of tumor lesion dimensions is ≥ 150% of the baseline value. The outcome is reported as the median with 95% confidence interval, as determined by Kaplan-Meier analysis and log-rank test. | 7.7 years | 
| Overall Survival (OS) | Overall survival (OS) rate is reported as number and percentage of participants remaining alive the date of transplant through each year, up to 5 years (reported as a number without dispersion). | After 1, 2, 3, 4, and 5 years | 
| Detection of Tumor-specific CD8-positve Memory T-cells Before and After Vaccination | Anti-tumor T-cell immune responses were evaluated by an in vitro evocative test on their peripheral blood mononuclear cell (PBMCs) before and after vaccination, as assessed by measurement of intracellular cytokines and/or intracellular perforin/granzyme in CD8+ T-cells, and/or CD137 induction on CD4+ T-cells. PBMCs were co-cultured with CpG-activated autologous MCL tumor cells and evaluated for tumor-specific immune responses as measured by CD137 expression on their T cells. The outcome is reported as the number of participants for whom tumor-specific memory CD8 cells were detected at baseline and after vaccination and transplant (numbers without dispersion). | Baseline and after vaccination and transplant, approximately 5 years | 
| Detection of Tumor-specific CD4-positve T-cells Before and After Vaccination | Anti-tumor T-cell immune responses were evaluated by an in vitro evocative test on their peripheral blood mononuclear cell (PBMCs) before and after vaccination, as assessed by measurement of intracellular cytokines and/or intracellular perforin/granzyme in CD8+ T-cells, and/or CD137 induction on CD4+ T-cells. PBMCs were co-cultured with CpG-activated autologous MCL tumor cells and evaluated for tumor-specific immune responses as measured by CD137 expression on their T cells. The outcome is reported as the number of participants for whom tumor-specific memory CD4 cells were detected at baseline and after transplant (numbers without dispersion). | Baseline and after vaccination and transplant, approximately 5 years |