Pharmacologic Pretransplant Immunosuppression (PTIS) + Reduced Toxicity Conditioning (RTC) Allogeneic Stem Cell Transplantation in Inherited Hematologic Disorders

To assess the outcomes of NRM when administering pharmacologic pretransplant immunosuppression (PTIS) followed by pretransplant reduced toxicity conditioning (RTC) and an allogeneic stem cell transplant (allo-SCT) and post-transplant graft-versus-host disease prophylaxis based on post-transplant cyclophosphamide (PT-Cy) in patients with inherited blood disorders.

Study Overview

• Status: Withdrawn
• Conditions: Stem Cell Transplantation
• Intervention / Treatment: Drug: Fludarabine; Drug: Dexamethasone; Drug: Cyclophosphamide; Drug: Bortezomib; Drug: Rituximab; Drug: Busulfan; Drug: Cyclophosphamide (Cy); Drug: Tacrolimus (or cyclosporine); Drug: Mycophenolate mofetil (MMF); Drug: Rabbit ATG

Detailed Description

Objectives

Primary:

To estimate the 100-day non-relapse mortality (NRM) rate when administering pharmacologic pretransplant immunosuppression (PTIS) followed by pretransplant reduced toxicity conditioning (RTC) and an allogeneic stem cell transplant (allo-SCT) and post-transplant graft-versus-host disease prophylaxis based on post-transplant cyclophosphamide (PT-Cy) in patients with inherited blood disorders.

Secondary outcomes include the following:

i. Immune reconstitution ii. Infectious complications iii. Quality of life (QOL) at 3 months,100 days, and 1 year post-transplant iv. OS, EFS, and GRFS v. Incidence of aGVHD at day 100. vi. Rate of chronic GVHD within the first-year post transplantation. vii. Rate of Graft failure

• Study Type: Interventional
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • M D Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. The first six patients will be ages >12 years old and <35 years old. Thereafter in a second stage, patients ages 2 to 50 years old will be included.
2. Patient with a matched related donor or who has a related haploidentical donor identified.
3. Performance score of at least 70 by Karnofsky or 0 to 1 by ECOG (age > 12 years), or Zubrod or Lansky Play Performance Scale of at least 70 (age <12 years).

4. Adequate major organ system function as demonstrated by:

   1. Serum creatinine clearance equal or more than 50 ml/min (calculated with Cockroft-Gault formula).
   2. Bilirubin equal or less than 1.5 mg/dl except for Gilbert's disease. ALT and/or AST equal or less than 3x institutional ULN. Conjugated (direct) bilirubin less than 2x upper limit of normal.
   3. Left ventricular ejection fraction equal or greater than 50%.
   4. Diffusing capacity for carbon monoxide (DLCO) equal or greater than 50%
   5. Predicted, corrected for hemoglobin. For children < 7 years of age who are unable to perform PFT, oxygen saturation > 92% on room air by pulse oximetry.
5. Patient or the patient's legal representative, parent(s) or guardian should be able to provide written informed consent. Assent of a minor if participant's age is at least seven and less than eighteen years.
6. Sexually active males and females of childbearing potential must agree to use a form of contraception considered effective and medically acceptable by the Investigator.

Exclusion Criteria:

1. HIV positive; active hepatitis B or C.
2. Uncontrolled infections.
3. Liver cirrhosis. However mild fibrosis will be allowed i.e. fine reticulin or Grade 1, with bridging fibrosis.
4. CNS involvement within 3 months.
5. Positive pregnancy test in a woman with child bearing potential defined as not post-menopausal for 12 months or no previous surgical sterilization.
6. Inability to comply with medical therapy or follow-up.
7. Will restrict eligibility to a maximum BMI of ≤40
8. Patient with a known history of allergic reactions to any constituents of the cell product, including a known history of allergic reactions to DMSO.
9. Prior allo-SCT
10. Other active malignancy/cancer diagnosis in remission for at least 2yrs. Malignancies not being excluded are as follows: Ductal carcinoma in situ (DCIS), Basal cell carcinoma (BCC), Cervical intraepithelial neoplasia (CIN)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase I: Sequential Pharmacological PTIS	Drug: Fludarabine; 40 mg/m2/day i.v.- by vein; Other Names: Fludara™; Drug: Dexamethasone; 25 mg/m2/day i.v.-by vein; Drug: Cyclophosphamide; 100 mg/m2 IV-by vein; Other Names: Cytoxan™; Drug: Bortezomib; Four doses of bortezomib at a dose of 1.3 mg/m2 -injection under the skin; Other Names: Velcade®; Drug: Rituximab; Four doses of rituximab at a dose of 375 mg/m2- by vein; Other Names: Rituxan®; Drug: Busulfan; 110 mg/m2 i.v-by vein; Other Names: Busulfex™; Drug: Cyclophosphamide (Cy); by vein; Other Names: Cytoxan™; Drug: Tacrolimus (or cyclosporine); by vein
Experimental: Phase II: RTC Regimen and GVHD Prophylaxis Based on Post-Cy	Drug: Fludarabine; 40 mg/m2/day i.v.- by vein; Other Names: Fludara™; Drug: Cyclophosphamide; 100 mg/m2 IV-by vein; Other Names: Cytoxan™; Drug: Busulfan; 110 mg/m2 i.v-by vein; Other Names: Busulfex™; Drug: Cyclophosphamide (Cy); by vein; Other Names: Cytoxan™; Drug: Tacrolimus (or cyclosporine); by vein; Drug: Mycophenolate mofetil (MMF); given by PO; Drug: Rabbit ATG; by vein

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
To determine the 100-day non-relapse mortality (NRM) rate when administering pharmacologic pretransplant immunosuppression (PTIS) followed by pretransplant reduced toxicity conditioning (RTC	through study completion, an average of 1 year

Collaborators and Investigators

• Sponsor: M.D. Anderson Cancer Center
• Investigators: Principal Investigator: Jeremy Ramdial, Ramdial, M.D. Anderson Cancer Center

Publications and helpful links

Helpful Links

• M D Anderson Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): March 2, 2022
• Primary Completion (Actual): September 18, 2023
• Study Completion (Actual): September 18, 2023

Study Registration Dates

• First Submitted: March 4, 2022
• First Submitted That Met QC Criteria: March 14, 2022
• First Posted (Actual): March 24, 2022

Study Record Updates

• Last Update Posted (Actual): September 21, 2023
• Last Update Submitted That Met QC Criteria: September 18, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hematologic Diseases; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological; Dermatologic Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Dexamethasone; Cyclophosphamide; Rituximab; Bortezomib; Fludarabine; Tacrolimus; Mycophenolic Acid; Busulfan; Thymoglobulin; Cyclosporine; Cyclosporins
• Other Study ID Numbers: 2021-0477; NCI-2022-02150 (Other Identifier: NCI-CTRP-Clinical Trial Reporting Registry)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No