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

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ClinicalTrials.gov Identifier: NCT02995330
Recruitment Status : Recruiting
First Posted : December 16, 2016
Last Update Posted : May 13, 2019
Sponsor:
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Prostate Cancer Procedure: Bone marrow transplantation Drug: Cytoxan Drug: testosterone cypionate Phase 1

Detailed Description:
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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Pilot Study of Sex-Mismatched Allogeneic Bone Marrow Transplantation for Men With Metastatic Castration-Resistant Prostate Cancer
Actual Study Start Date : February 9, 2017
Estimated Primary Completion Date : January 2020
Estimated Study Completion Date : January 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Bone marrow transplantation

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
Infused with non-T-cell depleted bone marrow from a related female donor on Day 0

Drug: Cytoxan
Cytoxan 50mg/kg IV on Days +3 and +4

Drug: testosterone cypionate
testosterone cypionate 400 mg IM will be administered on Day +60, +90, and +120 (every 30 days x 3 doses)
Other Name: testosterone




Primary Outcome Measures :
  1. PSA response [ Time Frame: 6 months ]
    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)


Secondary Outcome Measures :
  1. Transplant-related mortality [ Time Frame: 3 years ]
    Number of participants who experience transplant-related mortality (TRM) following alloBMT

  2. PSA response rate [ Time Frame: 3 years ]
    Proportion of patients achieving a PSA decline ≥ 50% according to Prostate Cancer Working Group (PCWG2) criteria

  3. Objective response rate [ Time Frame: 3 years ]
    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

  4. Time to PSA progression [ Time Frame: 3 years ]
    Time to PSA progression as defined by PCWG2 criteria

  5. Time to Clinical/radiographic progression [ Time Frame: 3 years ]
    Time to clinical/radiographic progression on CT and bone scan as defined by RECIST and PCWG2 criteria, respectively.

  6. Number of participants who experience acute graft-versus-host-disease (GVHD) [ Time Frame: 3 years ]
    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+)

  7. Number of participants who experience chronic GVHD [ Time Frame: 3 years ]
    Number of participants who experience chronic GVHD as defined by protocol.

  8. Number of participants with donor chimerism [ Time Frame: up to 60 days ]
    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.

  9. Number of participants with graft failure [ Time Frame: 3 years ]
    Number of participants with failure to engraft due to rejection by host lymphocytes.

  10. Effects of post-transplantation cyclophosphamide on the immune reconstitution of T cells, B cells, and NK cells [ Time Frame: 5 years ]
  11. Number of participants who develop HLA specific antibodies [ Time Frame: 5 years ]
    Number of participants who develop HLA specific antibodies after HLA mismatched, allogeneic partially HLA-mismatched bone marrow transplantation



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02995330


Contacts
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Contact: Connie Collins, RN 410-955-1017 ccolli23@jhmi.edu
Contact: Rehab AbdAllah 410-955-4042 rabdall1@jhmi.edu

Locations
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United States, Maryland
Johns Hopkins Hospital Recruiting
Baltimore, Maryland, United States, 21205
Contact: Connie Collins, RN    410-955-1017    ccolli23@jhmi.edu   
Sponsors and Collaborators
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Investigators
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Principal Investigator: Samuel Denmeade, MD Johns Hopkins University

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Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
ClinicalTrials.gov Identifier: NCT02995330     History of Changes
Other Study ID Numbers: J1608
IRB00086105 ( Other Identifier: JHMI-IRB )
First Posted: December 16, 2016    Key Record Dates
Last Update Posted: May 13, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins:
Metastatic Castration-Resistant Prostate Cancer
Bone Marrow Transplantation
Additional relevant MeSH terms:
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Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Genital Diseases, Male
Prostatic Diseases
Methyltestosterone
Cyclophosphamide
Testosterone
Testosterone undecanoate
Testosterone enanthate
Testosterone 17 beta-cypionate
Androgens
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Anabolic Agents
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Myeloablative Agonists