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T regulatory cells after non-myeloablative (using fludarabine, cyclophosphamide, and total body irradiation) umbilical cord transplant.

Non-myeloablative (using fludarabine, cyclophosphamide, and total body irradiation) umbilical cord transplant.

Fixed dose of nTreg cells will be infused on day 0 of transplant after the umbilical cord blood cells

T Regulatory cells

Fludarabine 30mg/m\^2 IV over 1 hour on days -6 through -2 from transplant

Cyclophosphamide 50 mg/kg IV over 2 hours on day -6 from transplant

Total Body Irradiation (TBI) 200 cGy administered on day -1 in a single fraction will be given at a dose rate of 10-19 cGy/minute prescribed to the midplane of the patient at the level of the umbilicus.

Total Body Irradiation

Claudio Brunstein, MD, PhD

This is a Simon's optimal two-stage phase II trial designed to estimate grade II-IV acute graft-versus-host disease (GVHD) after infusion of T regulatory (nTreg) in a fixed dose ratio to the combined CD3+ cell count of the two graft units in recipients of double UCB transplantation. The nTreg cells (manufactured from a 3rd cord blood unit) are infused on day 0 at least 1 hour after the 2nd unit of the double umbilical cord blood (UCB) transplant.

The nTreg cells require an 18 day (±2 days) lead time based on the planned transplant day. The combined CD3+ cell content from the two graft UCB units is enumerated upon thaw (day 0). The patient then receives the number of nTregs cells from the 3rd cord product to achieve a Treg:CD3+ cells ratio of 5:1. The nTreg cell dose depends on the CD3+ cell content of the two graft UCB graft units, but it will not exceed the highest dose level safely tested in the ongoing University of Minnesota phase I Treg dose escalation study MT 2006-01.

Treg Cells for AGVHD in Non-myeloablative UCB Transplant

T Regulatory Cell for Suppression of Acute Graft-vs-Host-Disease in Recipients of a Non-Myeloablative Umbilical Cord Blood Transplantation for Treatment of Hematological Malignancies

Determine if 3:1 ratio of Treg:CD3+ cells reduces the risk grade II-IV acute graft versus host disease of 20% by day 100 as compared to patients with hematological malignancy receiving same conditioning regimen and immunosuppression but no Tregs.

Compare the incidence of double and single unit chimerism at day +100 between Treg and controls

Compare the incidence of grade III-IV aGVHD between Treg and controls

Compare the incidence of viral and fungal infections at 1 year between Treg and controls

Compare the probability of survival at 1 year between Treg and controls

Compare the incidence of neutrophil recovery at day 42 between Treg and controls

Determine the incidence of treatment related mortality (TRM) at 6 months between Treg and controls

Compare the incidence of platelet recovery at 1 year between Treg and controls

Compare the incidence of chronic GVHD at 1 year between Treg and controls

Compare the incidence of relapse at 1 year between Treg and controls

National Institutes of Health (NIH)

National Cancer Institute (NCI)

Masonic Cancer Center, University of Minnesota

Skin and Connective Tissue Diseases

Melanoma

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Neuroendocrine Tumor

Neuroepithelioma

Immunotoxins

RFT5pdgA

Background:

* CD4+ cells are white blood cells that regulate the immune system by controlling the strength and quality of the immune response.
* CD25+ cells are a subset of CD4+ cells that suppress or prevent immune responses.
* RFT-5-dgA is an immunotoxin (substance that kills specific cells in the immune system) that kills CD25+ cells.
* In mouse studies, RFT-5-dgA showed anti-tumor activity in animals studies.

Objective: To determine whether the immune system of patients with metastatic melanoma (melanoma that has spread beyond the original site) can cause tumors to shrink if the patients are given RFT-5-dgA to remove their CD25+ cells.

Eligibility: Patients 18 years of age and older with metastatic melanoma whose disease has progressed after receiving standard treatment.

Design:

* Patients receive RFT-5-dgA through a vein every other day for a total of 3 doses (one treatment course). Patients have routine blood tests during the week of treatment.
* Four to 5 weeks after the last dose, patients are evaluated with a physical examination, blood tests and scans and x-rays to evaluate their tumor.
* Patients whose tumor has shrunk or remained stable may be offered additional treatment with RFT-5-dgA up to a total of four courses.
* Patients undergo leukapheresis or have several tubes of blood drawn from a vein to determine the effects of RFT-5-dgA on the immune system. This is done before the first dose of RFT-5-dgA, after the first three doses, and possibly during subsequent treatment courses in those patients who receive additional treatment. For leukapheresis, blood is collected through a needle in an arm vein and flows through a catheter into a machine that separates it into its components by spinning. The white cells are extracted and the rest of the blood is returned through another needle in the other arm.

Background:

* RFT5-dgA is an immunotoxin comprised of the IL-2Ra-specific murine IgG1 antibody RFT5 linked to deglycosylated ricin A chain (dgA) via the sterically hindered heterobifunctional disulfide linker SMPT (4-succinimidyl-oxycarbonyl-a-methyl-a-(2-pyridyldithio)-toluene).
* RFT5-dgA is a recombinant immunotoxin that selectively targets CD25 expressing cells in vivo. Further, treatment of human PBMC with RFT5-dgA in vitro results in the preferential depletion of CD25+ Treg cells.
* Depletion of Treg cells can enhance tumor protection to tumor-associated antigens expressed as self antigens and the RFT5-dgA immunotoxin had potent antitumor effects in SCID mice xenografted with L540 cells which express CD25.
* The MTD established in the phase I trial of RFT5-dgA was 15mg/m(2)/course IV.

Objectives:

* The primary objective is to determine whether objective clinical responses can be obtained in patients with metastatic melanoma following administration of RFT5-dgA.
* Secondary objectives will determine whether changes occur in levels of CD4+CD25+ regulatory T cells (Treg cells) in peripheral blood from before to after treatment and evaluate the toxicity profile of patients treated on this trial.

Eligibility:

* Patients greater than 18 years of age with measurable metastatic melanoma, an expected survival greater than three months, who have progressed after receiving standard therapy will be included.
* Standard clinical laboratory values must be normal for study inclusion and patients may not be pregnant, breast-feeding or require anticoagulation.
* Patients must be willing to undergo leukapheresis.
* Patients with active infections, other major medical disorders, HAMA levels greater than 1 ug/mL, or who have had prior radiotherapy or who have extensive lung disease will be excluded.

Design:

* Patients will receive 3 mg/m(2) RFT5-dgA intravenously every other day for a total of 3 doses (one course).
* Four to five weeks after the last dose, patients will undergo tumor evaluation, evaluation of changes in T-regulatory cells (CD4+CD25+cells and Foxp3 expression), and toxicity assessment.
* One additional course may be administered to patients with stable disease or partial or complete response.
* Up to 41 evaluable patients may be accrued to determine whether theRFT5-dgA can produce a modest response rate targeted to be 20 percent (p1=0.20)
* Enrollment reflects the anticipated enrollment. Actual enrollment is unknown due to no longer having access to the data as records were destroyed

RFT-5-dgA in Patients With Metastatic Melanoma

Phase II Evaluation of RFT5-dgA in Patients With Metastatic Melanoma

The primary objective is to determine whether objective clinical responses can be obtained in patients with metastatic melanoma following administration of RFT5-dgA

Secondary objectives will determine whether changes occur in levels of CD4+CD25+ regulatory T cells (Treg cells) in peripheral blood from before to after treatment and evaluate the toxicity profile of patients treated on this trial.

University of Texas Southwestern Medical Center

Sincere efforts were made to obtain the study data, but were unsuccessful as all study records have been destroyed

Data Not Able to be Obtained

Age, Categorical

Sex: Female, Male

Sincere efforts were made to obtain the study data, but were unsuccessful as all study records have been destroyed.

Dr. Ellen Vitetta

Clinical Responses Can be Obtained in Following Administration of RFT5-dgA

Determine Whether Changes Occur in Levels of CD4+CD25+ Regulatory T Cells (Treg Cells) in Peripheral Blood

Toxicity Profile

Sincere efforts were made to obtain the study data, but were unsuccessful as all study records have been destroyed. No study data are available

No Study Data Available

Overall Study

Respiratory Tract (Lung and Bronchial) Diseases

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Carcinoma, Squamous Cell

Breast Neoplasms

Triple Negative Breast Neoplasms

Uterine Cervical Neoplasms

Carcinoma, Renal Cell

Small Cell Lung Carcinoma

Head and Neck Neoplasms

Carcinoma

Neoplasms, Squamous Cell

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Urogenital Neoplasms

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Breast Diseases

Adenocarcinoma

Neoplasms, Glandular and Epithelial

Kidney Neoplasms

Urologic Neoplasms

Kidney Diseases

Urologic Diseases

Male Urogenital Diseases

Renal Cell Carcinoma

Small Cell Lung Cancer

Clear Cell Renal Cell Carcinoma

Antibodies

Antibodies, Monoclonal

Durvalumab

Atezolizumab

Immunoglobulins

Antineoplastic Agents, Immunological

Participants will receive AZD8701 intravenously, on Day 1, 3, 5 and 8 and then weekly for a maximum of 2 years.

Participants will receive AZD8701 (intravenously, on Day 1, 3, 5 and 8 and then weekly) and durvalumab (MEDI4736) intravenously monthly for a maximum of 2 years.

AZD8701

The purpose of this study is to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, Immunogenicity and Antitumor Activity of AZD8701 Alone and in Combination with Durvalumab (MEDI4736) in Adult Subjects with Select Advanced Solid Tumors

This is a Phase I, First in Human, multicentre, open-label, multiple arm study with dose escalations and expansions at selected doses. Dose-escalation will occur with AZD8701 in monotherapy (Part 1) and in combination with durvalumab (Part 3) in selected participants with HNSCC, TNBC, NSCLC, ccRCC, gastroesophageal cancer, melanoma, cervical cancer, small-cell lung cancer and/or participants with solid tumours who have demonstrated a response to prior PD-(L)1 treatment.

Disease specific expansions will occur with a selected dose of AZD8701 in participants with NSCLC (Part 2) and with a selected dose of AZD8701 and durvalumab in participants with TNBC and clear cell RCC (Part 4).

This is a Phase I, FIH, multicentre, open-label, multiple arm study. Dose-escalation will occur with AZD8701 in monotherapy and in combination with durvalumab in selected participants with HNSCC, TNBC, NSCLC, ccRCC, gastroesophgeal cancer, melanoma, cervical cancer, small-cell lung cancer and/or participants with solid tumours who have demonstrated a response to prior PD-(L)1 treatment.

Disease specific expansions will occur with a selected dose of AZD8701 in participants with NSCLC and with a selected dose of AZD8701 and durvalumab in participants with TNBC and clear cell RCC.

First Time in Human Study of AZD8701 With or Without Durvalumab in Participants With Advanced Solid Tumours

A Phase I First-in-Human Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics and Efficacy of AZD8701 Administered Intravenously as Monotherapy and in Combination With Durvaluamb (MEDI4736) in Participants With Advanced Solid Tumours.

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal.

All request will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

Determined according to Incidence and treatment related AEs and SAEs

Determined according to Incidence of DLTs (during the first 28 day cycle)

Determined according to Incidence of abnormal vital signs and laboratory parameters

Safety and tolerability of the MTD/OBD/MFD assessed through incidence of AEs and SAEs

The proportion of subjects achieving a confirmed complete or partial response according to RECIST 1.1 by investigator assessment

Time from start of study treatment to the date of objective disease progression or death (by any cause in the absence of progression)

Time from first documented response (that is subsequently confirmed) to the date of objective disease progression or death (by any cause in the absence of progression)

The proportion of subjects with a best response of CR or PR in the first 16 weeks or SD for at least 16 weeks according to RECIST 1.1 by investigator assessment

Time from the start of study treatment until the date of first documented response (which is subsequently confirmed)

Best percentage change from baseline in sum of the diameters of target lesions

The survival rate of subjects at 18 months from start of treatment

Maximum concentration (Cmax) of AZD8701 in plasma

Time to maximum concentration (tmax) of AZD8701 in plasma

Exposure to AZD8701 through measurement of area under the curve (AUC) in plasma

Maximum concentration (Cmax) of AZD8701 in urine

Time to maximum concentration (tmax) of AZD8701 in urine

Exposure to AZD8701 through measurement of area under the curve (AUC) in urine

Urine samples will be collected to assess urine concentrations of AZD8701 at a series of timepoints to derive renal clearance

Maximum concentration (Cmax) of Durvalumab in serum

Minimum concentration (Cmin) of Durvalumab in serum

Percentage change in FOXP3 mRNA expression from pre-treatment (baseline) to post treatment

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Treg Cells for AGVHD in Non-myeloablative UCB Transplant	NCT02118311	Hematologic Mal...	T Regulatory ce... Fludarabine Cyclophosphamid... Total Body Irra...	18 Years - 69 Years	Masonic Cancer Center, University of Minnesota
RFT-5-dgA in Patients With Metastatic Melanoma	NCT00314093	Metastatic Mela...	RFT5pdgA	18 Years -	University of Texas Southwestern Medical Center
First Time in Human Study of AZD8701 With or Without Durvalumab in Participants With Advanced Solid Tumours	NCT04504669	Clear Cell Rena... Non-Small-Cell ... Triple Negative... Squamous Cell C... Small Cell Lung... Gastroesophagea... Melanoma Cervical Cancer Advanced Solid ...	AZD8701 Durvalumab	18 Years - 101 Years	AstraZeneca
Treg Cells for AGVHD in Non-myeloablative UCB Transplant	NCT02118311	Hematologic Mal...	T Regulatory ce... Fludarabine Cyclophosphamid... Total Body Irra...	18 Years - 69 Years	Masonic Cancer Center, University of Minnesota
Safety and Efficacy of Listeria in Combination With Chemotherapy as Front-line Treatment for Malignant Pleural Mesothelioma	NCT01675765	Malignant Pleur...	Immunotherapy p... Immunotherapy w...	18 Years -	Aduro Biotech, Inc.
Leading in MPNs Beyond Ruxolitinib in Combo With T-Regs	NCT05423691	Myelofibrosis	CK0804	18 Years -	Cellenkos, Inc.
Safety and Efficacy of Combination Listeria/GVAX Immunotherapy in Pancreatic Cancer	NCT01417000	Metastatic Panc...	GVAX Pancreas CRS-207 Cyclophosphamid...	18 Years -	Aduro Biotech, Inc.

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