All patients will receive a CD3+/CD19+ depleted stem cell transplant. In this study, the investigators will use HLA mismatched unrelated or haploidentical related donor peripheral blood stem cells. Prior to transplantation, the marrow (90-95%) will be negatively selected for CD3/CD19 using the ClinicMACs® depletion device. The remaining (5-10%) will undergo CD45+RA+ depletion and be frozen for future use as an immune boost.

Subjects will undergo hematopoietic stem cell transplant utilizing CD3+/CD19+ depleted cells following conditioning therapy.

Negative selection for CD3+/CD19+ cells will be performed on the CliniMACS® depletion device.

CD3/CD19 depleted leukocytes

Negative selection for CD45RA will be performed on the CliniMACS® depletion device.

CD45RA depleted leukocytes

Hydroxyurea

Rituximab

Alemtuzumab

Fludarabine

Thiotepa

Paul Pszabolcs, MD

INDUCTION (Step 1): Participants will receive continuous treatment with relugolix + an androgen receptor pathway inhibitor (ARPI).

After 6-12 months of continuous treatment, participants whose PSA is ≤ 0.2 ng/mL and who have completed step two registration will be randomized to one of two treatment arms:

• Cohort A: Arm 1 will continue standard-of-care, continuous treatment with relugolix or androgen deprivation therapy (ADT) + ARPI per clinical investigator.

Step 1: Continuous treatment with relugolix + ARPI

relugolix + ARPI

Step 2: Standard-of-care, continuous treatment with relugolix or androgen deprivation therapy (ADT) + ARPI.

relugolix or androgen deprivation therapy (ADT) + ARPI

INDUCTION (Step 1): Participants will receive continuous treatment with relugolix + an androgen receptor pathway inhibitor (ARPI).

After 6-12 months of continuous treatment, participants whose PSA is ≤ 0.2 ng/mL and who have completed step two registration will be randomized to one of two treatment arms:

• Cohort A: Arm 2 will receive intermittent treatment with relugolix + ARPI.

Step 2: Intermittent treatment with relugolix + ARPI.

relugolix + ARPI.

Participants who have achieved PSA ≤ 0.2 ng/mL are eligible and will receive intermittent treatment with relugolix + ARPI.

Intermittent treatment with relugolix + ARPI.

Intermittent- Relugolix or androgen deprivation therapy (ADT) + ARPI

Erynn Peyton

Umang Swami, MD

* Patients with high-risk genetic features \&/or poor response to upfront therapy
* Myeloablative Conditioning (MAC): rabbit antithymocyte globulin (rATG), Busulfan, Fludarabine, and Thiotepa. All agents are administered intravenously. rATG is administered from days -9 to -7, followed by Busulfan and Fludarabine from days -6 to -3, \& Thiotepa on day -2 OR
* Reduced Intensity Conditioning (RIC): rabbit antithymocyte globulin (rATG), Fludarabine, Melphalan, and Thiotepa. All agents are administered intravenously. rATG is administered from days -9 to -7. Fludarabine is administered from day -8 to day -5, followed by Thiotepa on day -4 and Melphalan on days -3 and -2
* Patients will undergo infusion of the ex vivo TCRαβ/CD19+ depleted haploidentical HPC graft on day 0. On Day +7, patients will undergo infusion of the memory-like NK (ML NK) cells, followed by IL-2 subcutaneously 4 hours after the infusion. IL-2 will continue every other day through Day +19 for a maximum of 7 doses

* Patients with high-risk AML who meet certain criteria listed in the protocol
* Myeloablative Conditioning (MAC): rabbit antithymocyte globulin (rATG), Busulfan, Fludarabine, and Thiotepa. All agents are administered intravenously. rATG is administered from days -9 to -7, followed by Busulfan and Fludarabine from days -6 to -3, \& Thiotepa on day -2 OR
* Reduced Intensity Conditioning (RIC): rabbit antithymocyte globulin (rATG), Fludarabine, Melphalan, and Thiotepa. All agents are administered intravenously. rATG is administered from days -9 to -7. Fludarabine is administered from day -8 to day -5, followed by Thiotepa on day -4 and Melphalan on days -3 and -2
* Patients will undergo infusion of the ex vivo TCRαβ/CD19+ depleted haploidentical HPC graft on day 0. On Day +7, patients will undergo infusion of the memory-like NK (ML NK) cells, followed by IL-2 subcutaneously 4 hours after the infusion. IL-2 will continue every other day through Day +19 for a maximum of 7 doses

Donors who meet the eligibility criteria will be mobilized as per institutional standard practice using G-CSF 10 mcg/kg/day for 5 consecutive days. Leukapheresis will be performed after 5 days of G-CSF administration (on Day -1) with a target volume for collection of 20 liters. If additional collection days are necessary to ensure target CD34+ doses, G-CSF administration may be extended per institutional standard and adjusted per physician discretion. Up to 4 days of pheresis are permitted.

If suboptimal collection of stem cells is predicted, plerixafor may be administered at a dose of 0.24 mg/kg subcutaneous injection once (maximum 40mg/dose). For patients with renal impairment, plerixafor will be administered at a dose of 0.16 mg/kg subcutaneous injection (maximum 27 mg/day).

Plerixafor

G-CSF will be administered at a dose of 10 mcg/kg/day for 5 days, or 6 days if two days of collection are needed.

Granulocyte Colony-Stimulating Factor

Thomas M Pfeiffer, M.D.

Jeffrey Bednarski, M.D., Ph.D.

Amanda Cashen, M.D.

Todd Fehniger, M.D., Ph.D.

Shalini Shenoy, M.D.

Robert Hayashi, M.D.

Melissa Mavers, M.D., Ph.D.

Rachel Langley, PharmD

Feng Gao, Ph.D.

Each study participant will receive 3 injections of 4 µg GAD-alum (Diamyd). The first, second and third injection will be one month apart.

Vitamin D (Divisun 2000 IE) will be given from one month before the first injection of GAD-alum until one month after the third injection (120 days in total).

3 intra-inguinal injections (into the lymph nodes) of GAD-alum one month apart. Supplier Diamyd Medical AB in Stockholm, Sweden

recombinant human glutamic acid dehydrogenase (rhGAD65), formulated in aluminium hydrogel

1 tablet/day, total daily dose of 2000 IE given per os from day -30 through day 90. Supplier Meda, Solna, Sweden

Vitamin D

Norwegian University of Science and Technology

Participants in this group will undergo up to six months of systemic androgen deprivation therapy (ADT) and Androgen receptor signaling inhibitor (ARSI). During system therapy, participants will undergo five weeks of para-aortic radiation therapy.

Total participation duration is up to five years.

Participants will undergo five weeks of PA-RT daily, for up to 30 minutes per day for 25 days, Monday through Friday, consisting of a total dose of 50 grays (Gys) delivered in 25 fractions to the Clinical Tumor Volume (CTV).

Para Aortic Radiation Therapy: Photon Therapy

Participants will undergo five weeks of PA-RT daily, for up to 30 minutes per day for 25 days, Monday through Friday, consisting of a total dose of 60 to 65 Gys delivered in 25 fractions to the Gross Tumor Volume (GTVn).

Para Aortic Radiation Therapy: Proton Therapy

Androgen deprivation therapy will be administered as per standard of care.

Androgen Deprivation Therapy

Androgen receptor signaling inhibitor (ARSI) will be administered as per standard of care.

Androgen Receptor Signaling Inhibitor

Benjamin J Rich, MD

Alan Dal Pra, MD

The participants will take 2 tablets (300 mg each tablet) of study treatment (darolutamide) orally bid at about 12 hour intervals.

Darolutamide 600 mg twice daily

Androgen deprivation therapy (ADT) is a treatment that commonly used to lower the amount of hormones called androgens in the body.

Androgen deprivation therapy (ADT)

Participants with PSA level \<0.2 ng/mL after 6 months of treatment with Apalutamide and ADT during initial treatment phase, will enter main treatment phase and treated with apalutamide with intermittent ADT per protocol or followed up for at least 18 months from Day 1 of Cycle 7 (each cycle 28 days) and followed up for up to a maximum of 2 years after the main treatment phase, or until death, withdrawal of consent, loss to follow-up, early termination of the study by the sponsor for any reason, whichever occurs first.

Apalutamide will be administered orally from Day 1 of Cycle 1 till 6 months in initial treatment phase and then in main treatment phase from Day 1 of Cycle 7 up to at least 18 months.

Apalutamide

The choice of ADT will be at discretion of the Investigator. Dosing (dose and frequency of administration) will be consistent with the prescribing information.

Androgen-deprivation Therapy (ADT)

Participants with PSA level \<0.2 ng/mL after 6 months of treatment with Apalutamide and ADT during initial treatment phase, will enter main treatment phase and continue to receive apalutamide plus ADT or followed up for at least 18 months from Day 1 of Cycle 7 (each cycle 28 days) and followed up for up to a maximum of 2 years after the main treatment phase, or until death, withdrawal of consent, loss to follow-up, early termination of the study by the sponsor for any reason, whichever occurs first.

Male assigned at birth, inclusive of all gender identities.

* Treatment consists of adaptive dose-escalated stereotactic body radiotherapy (SBRT) to the pelvic nodes to 25 Gy in 5 once or twice weekly fractions with simultaneous integrated boosts (SIB) to the prostate and proximal seminal vesicles to 36.25 Gy in 5 fractions (full seminal vesicles if involved), to the prostate to 40 Gy in 5 fractions, and to the involved MR-detected nodule(s) to up to 50 Gy in 5 fractions.
* Androgen deprivation therapy (ADT) will be administered to study patients according to institutional standard. Unfavorable Intermediate-risk Disease: Patients should receive a minimum of 4 months of ADT. Patients can receive longer duration of ADT at the discretion of the treating physician. High-risk disease: Patients should receive a minimum of 1 year of ADT. Patients can receive up to 2 years of ADT at the discretion of the treating physician.

Device that will be used to administer radiotherapy

Ethos Varian treatment system

Radiotherapy interruptions are acceptable as long as treatments are no more than 16 days apart.

Adaptive stereotactic body radiotherapy

Androgen deprivation therapy (ADT) will be administered to study patients according to institutional standard. Patients should initiate ADT beginning no sooner than 60 days prior to start of radiation. ADT is defined as a GnRH agonist/antagonist (leuprolide, goserelin, degarelix, or relugolix). Patients treated with leuprolide, goserelin, or degarelix should also receive an androgen receptor antagonist (flutamide or bicalutamide) for 30 days from the start of GnRH agonist/antagonist or until the end of radiation, depending on institutional standard and physician preference.

Agent selection is per treating physician discretion and will be administered per institutional standard and FDA-approved labeling.

Androgen deprivation therapy

Participants received enzalutamide 160 mg capsules, orally once daily if tolerable, and continued ADT until radiographic disease progression was documented or until they started another investigational agent or new therapy for treatment of prostate cancer. Participants were to remain on study treatment until confirmed radiographic disease progression. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment.

Enzalutamide

All participants were required to maintain ADT during study treatment, either using luteinizing hormone-releasing hormone (LHRH) agonist/antagonist or having a history of bilateral orchiectomy.

Participants received enzalutamide-matching placebo capsules, orally once daily and continued ADT until radiographic disease progression was documented or until they started another investigational agent or new therapy for treatment of prostate cancer. Participants were to remain on study treatment until confirmed radiographic disease progression. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment."

Placebo

Participants who received placebo in double-blind phase and remaind on study treatment until confirmed radiographic disease progression received enzalutamide and continued ADT in open-label phase. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment.

To understand how darolutamide plus hormone therapy affects physical activity, we would like to specifically monitor the step count of men receiving these medications.

How darolutamide and hormone therapy affects the step count of older men who have prostate cancer

Darolutamide

How step count/physical activity affects certain quality of life changes these men experience such as differences in pain, mood, function, memory and fatigue

Physician choice Androgen Deprivation (Hormone) Therapy

Clinical Trials Intake

Russell Szmulewitz

Patients undergo TBI BID on days -10 to -7, and receive thiotepa IV over 3 hours on days -6 and -5, fludarabine IV over 30 to 60 minutes on days -6 to -2, tacrolimus (or cyclosporine or sirolimus if toxicities occur) IV continuously starting on day -1, CD34+ enriched CD45RA-depleted donor T-lymphocytes IV on day 0, and methotrexate IV on days 1, 3, 6, and 11. If there is no evidence of grade II-IV acute GVHD on or prior to day 50, tacrolimus (or cyclosporine or sirolimus) is tapered per month for capsules (or per week for liquid). Patients also undergo bone marrow aspiration/biopsy, ECHO or MUGA scan, and collection of blood samples throughout the trial.

Total-Body Irradiation

Tacrolimus

Allogeneic CD34+-enriched and CD45RA-depleted PBSCs

Methotrexate

Cyclosporine

Sirolimus

Bone Marrow Aspiration and Biopsy

Echocardiography

Multigated Acquisition Scan

Biospecimen Collection

Patients receive fludarabine IV over 30 to 60 minutes on days -6 to -2, busulfan IV over 180 minutes on days -5 to -2, and undergo TBI BID on day -1. Patients also receive tacrolimus (or cyclosporine or sirolimus if toxicities occur) IV continuously starting on day -1, CD34+ enriched CD45RA-depleted donor T-lymphocytes IV on day 0, and methotrexate IV on days 1, 3, 6, and 11. If there is no evidence of grade II-IV acute GVHD on or prior to day 50, tacrolimus (or cyclosporine or sirolimus) is tapered per month for capsules (or per week for liquid). Patients also undergo bone marrow aspiration/biopsy, ECHO or MUGA scan, and collection of blood samples throughout the trial.

Busulfan

Patients undergo TBI BID on days -4 to -2 or -3 to -1, and receive PBSC IV on day 0. Patients also receive cyclophosphamide IV over 1 to 2 hours on days 3 and 4, and tacrolimus (or cyclosporine or sirolimus if toxicities occur) IV continuously starting on day 5. If there is no evidence of grade II-IV acute GVHD on or prior to day 50, tacrolimus (or cyclosporine or sirolimus) is tapered per month for capsules (or per week for liquid). Patients also undergo bone marrow aspiration/biopsy, ECHO or MUGA scan, and collection of blood samples throughout the trial.

Cyclophosphamide

Peripheral Blood Stem Cell

Patients receive fludarabine IV over 30 to 60 minutes on days -5 to -2, busulfan IV over 180 minutes on days -5 to -2, PBSC IV on day 0, cyclophosphamide IV over 1 to 2 hours on days 3 and 4, and tacrolimus (or cyclosporine or sirolimus if toxicities occur) IV continuously starting on day 5. If there is no evidence of grade II-IV acute GVHD on or prior to day 50, tacrolimus (or cyclosporine or sirolimus) is tapered per month for capsules (or per week for liquid). Patients also undergo bone marrow aspiration/biopsy, ECHO or MUGA scan, and collection of blood samples throughout the trial.

Patients undergo TBI BID on days -6 to -4, and receive cyclophosphamide IV over 1 hour on days -3 to -2, tacrolimus (or cyclosporine or sirolimus if toxicities occur) IV continuously starting on day -1, PBSC IV on day 0, and methotrexate IV on days 1, 3, 6, and 11. If there is no evidence of grade II-IV acute GVHD on or prior to day 50, tacrolimus (or cyclosporine or sirolimus) is tapered per month for capsules (or per week for liquid). Patients also undergo bone marrow aspiration/biopsy, ECHO or MUGA scan, and collection of blood samples throughout the trial.

Patients receive busulfan IV over 180 minutes on days -8 to -5, cyclophosphamide IV over 1 hour on days -3 to -2, tacrolimus (or cyclosporine or sirolimus if toxicities occur) IV continuously starting on day -1, PBSC IV on day 0, and methotrexate IV on days 1, 3, 6, and 11. If there is no evidence of grade II-IV acute GVHD on or prior to day 50, tacrolimus (or cyclosporine or sirolimus) is tapered per month for capsules (or per week for liquid). Patients also undergo bone marrow aspiration/biopsy, ECHO or MUGA scan, and collection of blood samples throughout the trial.

Taiga Nishihori

Alison Sehgal

Marie Bleakley

* Participants will receive the standard of care. Standard systemic therapy (SST) and definitive local therapy (radiotherapy \[RT\] or radical prostatectomy \[RP\]) are the standard of care for de novo oligometastatic prostate cancer. This arm will be used to compare to the experimental arm.
* SST will begin 6 weeks of randomization and occur for 12 months. The definitive local therapy will be RT, with a small portion undergoing RP. Local therapy should be completed by the end of Week 20.

Standard androgen deprivation therapy (ADT) will be administered at the discretion of treating physician.

Standard androgen receptor signaling inhibitors (ARSI) will be administered at the discretion of the treating physician.

Androgen receptor signaling inhibitor (ARSI)

Local therapy will either be radiotherapy (RT) or radical prostatectomy (RP).

* Prostate +/- pelvic nodal radiation
* Radical prostatectomy + pelvic lymph node dissection

Local Therapy: Radical Prostatectomy (RP) or Radiotherapy (RT)

* Participants will receive the standard of care. Standard systemic therapy (SST) and definitive local therapy (radiotherapy \[RT\] or radical prostatectomy \[RP\]) are the standard of care for de novo oligometastatic prostate cancer. This arm will be used to compare to the experimental arm.
* SST will begin 6 weeks of randomization and occur for 12 months. The definitive local therapy will be RT, with a small portion undergoing RP. Local therapy should be completed by the end of Week 20.
* MDRT should be completed by the end of Week 24. Depending on the participant, there are different approaches to MDRT dosing and fraction size.

In participants randomized to the MDRT arm, MDRT to all lesions will be performed by the end of Week 24. Selection of a particular regimen (the dose and fractionation) will based on the size and location of the participant's metastatic site and the surrounding normal tissue constraints.

Metastasis directed radiotherapy (MDRT)

Angela Y Jia, MD, PhD

Christos Kyriakopoulos, MD

Participants will receive 6 months of standard-of-care androgen deprivation therapy (ADT) and radiation therapy.

Participants will receive 6 months of apalutamide and radiation therapy.

Participants will receive 24 months of standard-of-care androgen deprivation therapy (ADT) and radiation therapy.

Participants will receive 6 months of ADT, apalutamide, and radiation therapy.

CD3/CD19 결핍 백혈구, CD45RA 결핍 백혈구, 히드록시우레아, 리툭시맙, 알렘투주맙, 플루다라빈, 티오테파

렐루골릭스 + ARPI, 간헐적 - 렐루골릭스 또는 안드로겐 결핍 치료(ADT) + ARPI, 렐루골릭스 또는 안드로겐 결핍 치료(ADT) + ARPI, 렐루골릭스 + ARPI.

토끼 항티모사이트 글로불린, 부설판, 플루다라빈, 티오테파, 멜팔란, TCR 알파 베타/CD19+ 결핍 반일치 조혈 전구 세포 이식편, 기억 유사 자연 살해 세포, IL-2, 플레릭사포르, 과립구 집락 자극 인자, 클리니맥스

알루미늄 하이드로젤로 제조된 재조합 인간 글루타민산 탈수소효소(rhGAD65), 비타민 D

대동맥 주변 방사선 치료: 광자 치료, 대동맥 주변 방사선 치료: 양성자 치료, 안드로겐 결핍 치료, 안드로겐 수용체 신호 전달 억제제

다롤루타미드 600mg 하루 두 번, 안드로겐 결핍 치료(ADT)

아팔루타미드, 안드로겐 결핍 치료(ADT)

에토스 바리안 치료 시스템, 적응형 입체 방사선 치료, 안드로겐 결핍 치료

엔잘루타미드, 위약, 안드로겐 결핍 치료(ADT)

다롤루타미드, 의사 선택 안드로겐 결핍(호르몬) 치료

안드로겐 결핍 치료(ADT), 안드로겐 수용체 신호 전달 억제제(ARSI), 국소 치료: 근치적 전립선 절제술(RP) 또는 방사선 치료(RT), 전이 지향 방사선 치료(MDRT)

아팔루타미드, 안드로겐 결핍 치료