Sex-Mismatched Allogeneic Bone Marrow Transplantation for Men With Metastatic Castration-Resistant Prostate Cancer

Study Overview
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Brief Summary
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Men with progressive metastatic Castration-Resistant Prostate Cancer post first-line treatment with either androgen deprivation therapy alone or androgen deprivation therapy plus docetaxel who have an identified related female donor (mother sister, daughter, second degree relative such as granddaughter or niece) will undergo bone marrow transplantation followed by post-transplant Cytoxan (PT/Cy) and testosterone.

Detailed Description
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Men will undergo pre-transplant screening evaluation and be enrolled in the study. Subjects will be treated with a standard non-myeloablative conditioning regimen consisting of Fludarabine 30 mg/m2 IV Days -6 to -2; Cy 14.5 mg/kg IV Days -6 and -5; Total body irradiation (TBI) 200 cGy Day -1. On Day 0, patients will be infused with non-T-cell depleted bone marrow from a related female donor. Patients will receive GVHD prophylaxis consisting of: Cy 50mg/kg IV on Days +3 and +4; tacrolimus (IV or PO) beginning on Day +5 [dose adjusted to maintain trough level of 5-15 ng/mL] through day+180; Mycophenolate mofetil (MMF) 15 mg/kg PO TID, with a maximum dose of 1g TID beginning on Day +5 through Day +35. Patients will receive filgrastim (G-CSF) 5 mcg/kg/day beginning on Day +5 and continued until ANC ≥ 1500/mm3. Lastly, to produce maintenance tumor antigen stimulation, patients will be maintained on continuous LHRH agonist/antagonist therapy (if not previously surgically castrated) to suppress endogenous testosterone production throughout the treatment period; testosterone cypionate 400 mg IM will be administered on Day +60, +90, and +120 (every 30 days x 3 doses). Patients who achieve biochemical CR will stop LHRH agonist/antagonist treatment at day 180. Patients will be followed for 3 years post-BMT.

Official Title
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A Pilot Study of Sex-Mismatched Allogeneic Bone Marrow Transplantation for Men With Metastatic Castration-Resistant Prostate Cancer

Conditions
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Prostate Cancer

Intervention / Treatment
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* Procedure: Bone marrow transplantation
* Drug: Cytoxan
* Drug: testosterone cypionate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Performance status ≤1 Age ≥18 years and ≤ 75 years old Histologically-confirmed adenocarcinoma of the prostate Treated with continuous androgen ablative therapy (either surgical castration or LHRH agonist/antagonist) with documented castrate level of serum testosterone (<50 ng/dl) Metastatic disease radiographically documented by CT or bone scan Patient must be HLA typed at high resolution using DNA based typing at the following loci: HLA-A, -B, -C, and DRB1 Patient must have available one or more potential first (biologic mother, sister, half-sister, or daughter) or second-degree related female donor. Mothers and daughters have a 100% chance of being haploidentical matches, sisters a 75% chance of being matched or haploidentical, and second degree relatives have a 50% chance of being haploidentical matches. The donor and recipient must be HLA identical for at least one antigen at HLA-A, -B, -C and HLA-DRB1. Screening PSA must be ≥ 1.0 ng/mL. Prior therapy with one second line hormonal therapy is allowed (i.e. bicalutamide, nilutamide, flutamide, ketoconazole, abiraterone, enzalutamide, ARN-509). Prior docetaxel (≤ 6 cycles) as first line therapy Cardiac ejection fraction at rest must be ≥ 40% Acceptable liver function: Bilirubin < 2.5 mg/dL (unless due to Gilbert's disease, AST (SGOT) and ALT (SGPT) < 5 times upper limit of normal. Acceptable renal function: Serum creatinine within normal range. Pulmonary function: DLCO (corrected for hemoglobin), FEV1 and FVC >50% predicted. At least 4 wks since prior radiation or surgery with full recovery (no persistent toxicity ≥ Grade 1) Ability to understand and willingness to sign a written informed consent document. Exclusion Criteria: Prior treatment with Sipuleucel-T, radium-223, strontium-89, or samarium-153 Prior chemotherapy (docetaxel, cabazitaxel) for castrate resistant prostate cancer Evidence of serious and/or unstable pre-existing medical, psychiatric or other condition (including laboratory abnormalities) that could interfere with patient safety or provision of informed consent to participate in this study Active uncontrolled infection, including known history of HIV/AIDS or hepatitis B or C. Any psychological, familial, sociological, or geographical condition that could potentially interfere with compliance with the study protocol and follow-up schedule.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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Male

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: Bone marrow transplantation<br>Bone marrow transplantation followed by Cytoxan and testosterone Day -6 to -1: Subjects will be treated with a standard non-myeloablative conditioning regimen Day 0: subjects will be infused with non-T-cell depleted bone marrow from a related female donor. Subjects will receive GVHD prophylaxis consisting of: Day +3 and +4: Cytoxan (Cy) 50mg/kg IV Day +5 through Day +180: tacrolimus (IV or PO) beginning [dose adjusted to maintain trough level of 5-15 ng/mL] Day +5 through Day +35: Mycophenolate mofetil (MMF) 15 mg/kg PO TID, with a maximum dose of 1g TID. Day +5: filgrastim (G-CSF) 5 mcg/kg/day, continued until ANC ≥ 1500/mm3. Day +60, +90, and +120: testosterone cypionate 400 mg IM every 30 days x 3 doses Subjects will be maintained on continuous LHRH agonist/antagonist therapy (if not previously surgically castrated). Subjects who achieve biochemical CR will stop LHRH agonist/antagonist treatmentat day 180. | Procedure: Bone marrow transplantation<br>* Infused with non-T-cell depleted bone marrow from a related female donor on Day 0<br>Drug: Cytoxan<br>* Cytoxan 50mg/kg IV on Days +3 and +4<br>Drug: testosterone cypionate<br>* testosterone cypionate 400 mg IM will be administered on Day +60, +90, and +120 (every 30 days x 3 doses)<br>* Other names: testosterone;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PSA response | Percentage of participants with complete biochemical response at 6 months post-transplant (PSA <0.1 ng/mL for patients post-prostatectomy and PSA < 1 ng/mL for patients post-radiation therapy) | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Transplant-related mortality | Number of participants who experience transplant-related mortality (TRM) following alloBMT | 3 years | 
| PSA response rate | Proportion of patients achieving a PSA decline ≥ 50% according to Prostate Cancer Working Group (PCWG2) criteria | 3 years | 
| Objective response rate | Percentage of participants with reduction in measurable disease on CT scan as defined by RECIST criteria: Complete Response (CR)= disappearance of all target lesions; Partial Response (PR)= at least a 30% decrease in the sum of the largest diameter (LD) of target lesions, taking as reference the baseline sum LD; Progressive Disease (PD)= at least 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions; Stable disease (SD)= Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started | 3 years | 
| Time to PSA progression | Time to PSA progression as defined by PCWG2 criteria | 3 years | 
| Time to Clinical/radiographic progression | Time to clinical/radiographic progression on CT and bone scan as defined by RECIST and PCWG2 criteria, respectively. | 3 years | 
| Number of participants who experience acute graft-versus-host-disease (GVHD) | Number of participants with acute GVHD grades 2-4 and grades 3-4 as defined by Przepiorka criteria. Przepiorka criteria stages the degree of organ involvement in the skin, liver and gastrointestinal (GI) tract, based on severity, with Stage 1+ being least sever and Stage 4+ being most severe. Grading of acute GVHD is as follows: Grade I (skin involvement stages 1+ to 2+, with no liver or GI involvement), Grade II (skin involvement stages 1+ to 3+, liver 1+, GI tract 1+), Grade III (skin involvement stages 2+ to 3+, liver 1+, GI tract 2+ to 4+), Grade IV (skin involvement stages 4+, liver 4+) | 3 years | 
| Number of participants who experience chronic GVHD | Number of participants who experience chronic GVHD as defined by protocol. | 3 years | 
| Number of participants with donor chimerism | Patients with any amount of donor chimerism around day 60 will be considered as having engrafted. Chimerism determinations will be made on peripheral blood by a number of different methods depending on the specific patient. Methods may include (i) the usual standard of restriction fragment length polymorphism (RFLP) if the donor and recipient RFLPs are informative, (ii) fluorescence in-situ hybridization (FISH) for Y-chromosome markers on PBMC if the donor is male, (iii) cytogenetic analysis, (iv) flow cytometric analysis of HLA-A, B or DR on lymphocytes in the peripheral blood if haploidentical and suitable reagents exist or (v) PCR analysis of variable nucleotide tandem repeats (VNTR) in PBMC if informative. Mixed donor chimerism will be defined as >0%, but <95%. Complete donor chimerism will be defined as >95%. Patients who have relapsed or died prior to day 60 will not be evaluable for full donor chimerism, as these are competing risk factors. | up to 60 days | 
| Number of participants with graft failure | Number of participants with failure to engraft due to rejection by host lymphocytes. | 3 years | 
| Effects of post-transplantation cyclophosphamide on the immune reconstitution of T cells, B cells, and NK cells |  | 5 years | 
| Number of participants who develop HLA specific antibodies | Number of participants who develop HLA specific antibodies after HLA mismatched, allogeneic partially HLA-mismatched bone marrow transplantation | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metastatic Castration-Resistant Prostate Cancer, Bone Marrow Transplantation