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

Primary Purpose

Prostate Cancer

Status

Terminated

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Bone marrow transplantation

Cytoxan

testosterone cypionate

About this trial

This is an interventional treatment trial for Prostate Cancer focused on measuring Metastatic Castration-Resistant Prostate Cancer, Bone Marrow Transplantation

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)MaleDoes not accept healthy volunteers

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.

Sites / Locations

Johns Hopkins Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Bone marrow transplantation

Arm Description

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.

Outcomes

Primary Outcome Measures

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)

Secondary Outcome Measures

Transplant-related mortality

Number of participants who experience transplant-related mortality (TRM) following alloBMT

PSA response rate

Proportion of patients achieving a PSA decline ≥ 50% according to Prostate Cancer Working Group (PCWG2) criteria

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

Time to PSA progression

Time to PSA progression as defined by PCWG2 criteria

Time to Clinical/radiographic progression

Time to clinical/radiographic progression on CT and bone scan as defined by RECIST and PCWG2 criteria, respectively.

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+)

Number of participants who experience chronic GVHD

Number of participants who experience chronic GVHD as defined by protocol.

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.

Number of participants with graft failure

Number of participants with failure to engraft due to rejection by host lymphocytes.

Effects of post-transplantation cyclophosphamide on the immune reconstitution of T cells, B cells, and NK cells

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

Full Information

NCT ID

NCT02995330

First Posted

December 14, 2016

Last Updated

July 1, 2021

Sponsor

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

1. Study Identification

Unique Protocol Identification Number

NCT02995330

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

July 2021

Overall Recruitment Status

Terminated

Why Stopped

lack of accrual

Study Start Date

February 9, 2017 (Actual)

Primary Completion Date

June 16, 2021 (Actual)

Study Completion Date

June 16, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Prostate Cancer

Keywords

Metastatic Castration-Resistant Prostate Cancer, Bone Marrow Transplantation

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

3 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Bone marrow transplantation

Arm Type

Experimental

Arm Description

Intervention Type

Procedure

Intervention Name(s)

Bone marrow transplantation

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Cytoxan

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

testosterone cypionate

Other Intervention Name(s)

testosterone

Intervention Description

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

Primary Outcome Measure Information:

Title

PSA response

Description

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)

Time Frame

6 months

Secondary Outcome Measure Information:

Title

Transplant-related mortality

Description

Number of participants who experience transplant-related mortality (TRM) following alloBMT

Time Frame

3 years

Title

PSA response rate

Description

Proportion of patients achieving a PSA decline ≥ 50% according to Prostate Cancer Working Group (PCWG2) criteria

Time Frame

3 years

Title

Objective response rate

Description

Time Frame

3 years

Title

Time to PSA progression

Description

Time to PSA progression as defined by PCWG2 criteria

Time Frame

3 years

Title

Time to Clinical/radiographic progression

Description

Time to clinical/radiographic progression on CT and bone scan as defined by RECIST and PCWG2 criteria, respectively.

Time Frame

3 years

Title

Number of participants who experience acute graft-versus-host-disease (GVHD)

Description

Time Frame

3 years

Title

Number of participants who experience chronic GVHD

Description

Number of participants who experience chronic GVHD as defined by protocol.

Time Frame

3 years

Title

Number of participants with donor chimerism

Description

Time Frame

up to 60 days

Title

Number of participants with graft failure

Description

Number of participants with failure to engraft due to rejection by host lymphocytes.

Time Frame

3 years

Title

Effects of post-transplantation cyclophosphamide on the immune reconstitution of T cells, B cells, and NK cells

Time Frame

5 years

Title

Number of participants who develop HLA specific antibodies

Description

Number of participants who develop HLA specific antibodies after HLA mismatched, allogeneic partially HLA-mismatched bone marrow transplantation

Time Frame

5 years

10. Eligibility

Sex

Male

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

Eligibility 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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Samuel Denmeade, MD

Organizational Affiliation

Johns Hopkins University

Official's Role

Principal Investigator

Facility Information:

Facility Name

Johns Hopkins Hospital

City

Baltimore

State/Province

Maryland

ZIP/Postal Code

21205

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

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

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