Donor Stem Cell Transplant After Chemotherapy for the Treatment of Recurrent or Refractory High-Risk Solid Tumors in Pediatric and Adolescent-Young Adults

Phase 2

Terminated

• Conditions: Refractory Malignant Peripheral Nerve Sheath Tumor; Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Neuroblastoma; Recurrent Rhabdomyosarcoma; Refractory Malignant Solid Neoplasm; Desmoplastic Small Round Cell Tumor; Recurrent Malignant Peripheral Nerve Sheath Tumor; Refractory Desmoplastic Small Round Cell Tumor; Recurrent Desmoplastic Small Round Cell Tumor; Recurrent Malignant Solid Neoplasm
• Interventions: Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Drug: Cyclosporine; Drug: Etoposide; Drug: Fludarabine Phosphate; Biological: Lapine T-Lymphocyte Immune Globulin; Drug: Melphalan; Drug: Mycophenolate Mofetil; Drug: Tacrolimus; Drug: Thiotepa

• Registration Number: NCT04530487
• Lead Sponsor: M.D. Anderson Cancer Center

Brief Summary

This phase II trial investigates side effects and how well donor stem cell transplant after chemotherapy works in treating pediatric and adolescent-young adults with high-risk solid tumor that has come back (recurrent) or does not respond to treatment (refractory). Chemotherapy drugs, such as fludarabine, thiotepa, etoposide, melphalan, and rabbit anti-thymo...

Detailed Description

PRIMARY OBJECTIVE:
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Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study Start: 2020-08-19
• Study First Submitted: 2020-08-25
• Study First Submitted QC: 2020-08-25
• Study First Posted: 2020-08-28
• Status Verified: 2024-08
• Primary Completion: 2024-08-26
• Study Completion: 2024-08-26
• Last Update Submitted: 2024-10-23
• Last Update Posted: 2024-10-26

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 40

Inclusion Criteria

• Pathological criteria, including malignant recurrent/refractory solid tumors. This would include:

  • Ewing's/peripheral primitive neuroectodermal tumor (PNET)
  • Malignant peripheral nerve sheath tumor, neurofibrosarcoma
  • Rhabdomyosarcoma
  • Neuroblastoma (patients who are ineligible for tandem autologous transplant or who are at least 3 months post autologous HCT)
  • Desmoplastic small round cell tumor (DSRCT)- both new diagnoses as well as recurrent/refractory disease

• Patients must have chemo-responsive disease, defined as; 30% or greater decrease in the tumor target lesions when compared to its pre-treatment evaluation. Patients with complete response will be eligible to participate

• Available suitable HCT donor

• Creatinine clearance or glomerular filtration rate (GFR) >= 50 ml/min/1.73m^2, and not requiring dialysis

• Diffusing capacity of lung for carbon monoxide (DLCO) (corrected for hemoglobin) >= 50% predicted. If unable to perform pulmonary function tests, then oxygen (O2) saturation >= 92% in room air

• Bilirubin =< 3 x upper limit of normal (ULN) and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 5 x for age (with the exception of isolated hyperbilirubinemia due to Gilbert's syndrome)

• DONOR: Matched related donor bone marrow (10 of 10 HLA alleles [HLA-A, B, C, DR, and DQ]. Matched related donor peripheral blood stem cell (PBSC) is allowed only if collection of bone marrow (BM) is not available or refused by parents/donor

• DONOR: Matched allogeneic umbilical cord blood (UCB): related

  • High-resolution matching at A,B, DRB1 (minimum 4/6)
  • KIR major histocompatibility complex (MHC) class 1 preferential mismatch (minimum 4/6)

• DONOR: Matched allogeneic umbilical cord blood: unrelated

  • High-resolution matching at A,B, DRB1 (minimum 4/6) •*KIR MHC class 1 preferential mismatch (minimum 4/6)

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Exclusion Criteria

• Lack of histocompatible suitable related donor/ graft source
• End-organ failure that precludes the ability to tolerate the transplant procedure, including conditioning regimen
• Renal failure requiring dialysis
• Congenital heart disease resulting in congestive heart failure
• Ventilatory failure: requires invasive mechanical ventilation
• Human immunodeficiency virus (HIV) infection
• Uncontrolled bacterial, viral, or fungal infections (currently taking medication yet clinical symptoms progress); stable, controlled disease with treatment is not an exclusion criteria
• A female of reproductive potential who is pregnant, planning to become pregnant during the study, or is nursing a child
• Any patient who does not fulfill the inclusion criteria listed above

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (conditioning regimen, HSCT)	Allogeneic Hematopoietic Stem Cell Transplantation	CONDITIONING REGIMEN: Patients receive thiotepa IV over 2-4 hours, etoposide IV over 60 minutes on days -8 to -6, melphalan IV over 20 minutes on days -5 and -4, and fludarabine phosphate IV over 1 hour on days -5 to -3 in the absence of disease progression or unacceptable toxicity. Patients receiving umbilical cord transplant also receive rabbit anti-thymocyte globulin IV on days -3 and -4. TRANSPLANT: Patients undergo HSCT on day 0. GVHD PROPHYLAXIS: Beginning day -2, patients receive tacrolimus or cyclosporine IV continuously until able to receive PO. Patients continue tacrolimus or cyclosporine PO to day 60 and tapered to day 100. Patients also receive mycophenolate mofetil PO or IV every 8 hours until day 40 and tapered to day 90.
Treatment (conditioning regimen, HSCT)	Cyclosporine	CONDITIONING REGIMEN: Patients receive thiotepa IV over 2-4 hours, etoposide IV over 60 minutes on days -8 to -6, melphalan IV over 20 minutes on days -5 and -4, and fludarabine phosphate IV over 1 hour on days -5 to -3 in the absence of disease progression or unacceptable toxicity. Patients receiving umbilical cord transplant also receive rabbit anti-thymocyte globulin IV on days -3 and -4. TRANSPLANT: Patients undergo HSCT on day 0. GVHD PROPHYLAXIS: Beginning day -2, patients receive tacrolimus or cyclosporine IV continuously until able to receive PO. Patients continue tacrolimus or cyclosporine PO to day 60 and tapered to day 100. Patients also receive mycophenolate mofetil PO or IV every 8 hours until day 40 and tapered to day 90.
Treatment (conditioning regimen, HSCT)	Etoposide	CONDITIONING REGIMEN: Patients receive thiotepa IV over 2-4 hours, etoposide IV over 60 minutes on days -8 to -6, melphalan IV over 20 minutes on days -5 and -4, and fludarabine phosphate IV over 1 hour on days -5 to -3 in the absence of disease progression or unacceptable toxicity. Patients receiving umbilical cord transplant also receive rabbit anti-thymocyte globulin IV on days -3 and -4. TRANSPLANT: Patients undergo HSCT on day 0. GVHD PROPHYLAXIS: Beginning day -2, patients receive tacrolimus or cyclosporine IV continuously until able to receive PO. Patients continue tacrolimus or cyclosporine PO to day 60 and tapered to day 100. Patients also receive mycophenolate mofetil PO or IV every 8 hours until day 40 and tapered to day 90.
Treatment (conditioning regimen, HSCT)	Fludarabine Phosphate	CONDITIONING REGIMEN: Patients receive thiotepa IV over 2-4 hours, etoposide IV over 60 minutes on days -8 to -6, melphalan IV over 20 minutes on days -5 and -4, and fludarabine phosphate IV over 1 hour on days -5 to -3 in the absence of disease progression or unacceptable toxicity. Patients receiving umbilical cord transplant also receive rabbit anti-thymocyte globulin IV on days -3 and -4. TRANSPLANT: Patients undergo HSCT on day 0. GVHD PROPHYLAXIS: Beginning day -2, patients receive tacrolimus or cyclosporine IV continuously until able to receive PO. Patients continue tacrolimus or cyclosporine PO to day 60 and tapered to day 100. Patients also receive mycophenolate mofetil PO or IV every 8 hours until day 40 and tapered to day 90.
Treatment (conditioning regimen, HSCT)	Lapine T-Lymphocyte Immune Globulin	CONDITIONING REGIMEN: Patients receive thiotepa IV over 2-4 hours, etoposide IV over 60 minutes on days -8 to -6, melphalan IV over 20 minutes on days -5 and -4, and fludarabine phosphate IV over 1 hour on days -5 to -3 in the absence of disease progression or unacceptable toxicity. Patients receiving umbilical cord transplant also receive rabbit anti-thymocyte globulin IV on days -3 and -4. TRANSPLANT: Patients undergo HSCT on day 0. GVHD PROPHYLAXIS: Beginning day -2, patients receive tacrolimus or cyclosporine IV continuously until able to receive PO. Patients continue tacrolimus or cyclosporine PO to day 60 and tapered to day 100. Patients also receive mycophenolate mofetil PO or IV every 8 hours until day 40 and tapered to day 90.
Treatment (conditioning regimen, HSCT)	Melphalan	CONDITIONING REGIMEN: Patients receive thiotepa IV over 2-4 hours, etoposide IV over 60 minutes on days -8 to -6, melphalan IV over 20 minutes on days -5 and -4, and fludarabine phosphate IV over 1 hour on days -5 to -3 in the absence of disease progression or unacceptable toxicity. Patients receiving umbilical cord transplant also receive rabbit anti-thymocyte globulin IV on days -3 and -4. TRANSPLANT: Patients undergo HSCT on day 0. GVHD PROPHYLAXIS: Beginning day -2, patients receive tacrolimus or cyclosporine IV continuously until able to receive PO. Patients continue tacrolimus or cyclosporine PO to day 60 and tapered to day 100. Patients also receive mycophenolate mofetil PO or IV every 8 hours until day 40 and tapered to day 90.
Treatment (conditioning regimen, HSCT)	Mycophenolate Mofetil	CONDITIONING REGIMEN: Patients receive thiotepa IV over 2-4 hours, etoposide IV over 60 minutes on days -8 to -6, melphalan IV over 20 minutes on days -5 and -4, and fludarabine phosphate IV over 1 hour on days -5 to -3 in the absence of disease progression or unacceptable toxicity. Patients receiving umbilical cord transplant also receive rabbit anti-thymocyte globulin IV on days -3 and -4. TRANSPLANT: Patients undergo HSCT on day 0. GVHD PROPHYLAXIS: Beginning day -2, patients receive tacrolimus or cyclosporine IV continuously until able to receive PO. Patients continue tacrolimus or cyclosporine PO to day 60 and tapered to day 100. Patients also receive mycophenolate mofetil PO or IV every 8 hours until day 40 and tapered to day 90.
Treatment (conditioning regimen, HSCT)	Tacrolimus	CONDITIONING REGIMEN: Patients receive thiotepa IV over 2-4 hours, etoposide IV over 60 minutes on days -8 to -6, melphalan IV over 20 minutes on days -5 and -4, and fludarabine phosphate IV over 1 hour on days -5 to -3 in the absence of disease progression or unacceptable toxicity. Patients receiving umbilical cord transplant also receive rabbit anti-thymocyte globulin IV on days -3 and -4. TRANSPLANT: Patients undergo HSCT on day 0. GVHD PROPHYLAXIS: Beginning day -2, patients receive tacrolimus or cyclosporine IV continuously until able to receive PO. Patients continue tacrolimus or cyclosporine PO to day 60 and tapered to day 100. Patients also receive mycophenolate mofetil PO or IV every 8 hours until day 40 and tapered to day 90.
Treatment (conditioning regimen, HSCT)	Thiotepa	CONDITIONING REGIMEN: Patients receive thiotepa IV over 2-4 hours, etoposide IV over 60 minutes on days -8 to -6, melphalan IV over 20 minutes on days -5 and -4, and fludarabine phosphate IV over 1 hour on days -5 to -3 in the absence of disease progression or unacceptable toxicity. Patients receiving umbilical cord transplant also receive rabbit anti-thymocyte globulin IV on days -3 and -4. TRANSPLANT: Patients undergo HSCT on day 0. GVHD PROPHYLAXIS: Beginning day -2, patients receive tacrolimus or cyclosporine IV continuously until able to receive PO. Patients continue tacrolimus or cyclosporine PO to day 60 and tapered to day 100. Patients also receive mycophenolate mofetil PO or IV every 8 hours until day 40 and tapered to day 90.

Primary Outcome Measures

Name	Time	Method
Rate of grade III or higher organ toxicity attributable to conditioning	Up to 30 days	Assessed using the Bearman Regimen-Related Toxicities Scale. The proportion of patients with 30-day grade III or higher organ toxicity will be reported together with the corresponding 95% Bayesian credible interval.
Transplant-related mortality (TRM)	At 30 days	The proportion of patients with 30-day TRM will be reported together with the corresponding 95% Bayesian credible interval.

Secondary Outcome Measures

Name	Time	Method
Rate of grade II organ toxicity	Up to 100 days post transplant	The 100-day rates of grade II organ toxicity will be reported as counts with percentages.
PFS	At 1 year post transplant	Will be calculated and illustrated from the time of transplant by the method of Kaplan and Meier.
Time to platelet and neutrophil engraftment	Up to 1 year post transplant	Will be calculated and illustrated from the time of transplant by the method of Kaplan and Meier.
Rate of infectious complications	Up to 100 days post transplant	The 100-day rates of infectious complications will be reported as counts with percentages.
Progression-free survival (PFS)	At 180 days post transplant	Will be assessed using the method of Kaplan and Meier.
Incidence of acute graft versus host disease (aGVHD)	At 100 days post transplant	The 100-day rates of acute with the competing risk of relapse will be estimated using the method of Gooley.
Overall survival (OS)	At 100 days post transplant	Will be calculated and illustrated from the time of transplant by the method of Kaplan and Meier.
OS	At 1 year post transplant	Will be calculated and illustrated from the time of transplant by the method of Kaplan and Meier.
Incidence of chronic GVHD	At 1 year post transplant	The 1 year rates of chronic GVHD with the competing risk of relapse will be estimated using the method of Gooley.
Rate of graft failure (primary and secondary)	Up to 100 days post transplant	The 100-day rates of primary and secondary graft failure will be reported as counts with percentages.
Incidence of relapse	At 1 year post transplant	Will be calculated and illustrated from the time of transplant by the method of Kaplan and Meier.

Trial Locations

Locations (1)

M D Anderson Cancer Center; 🇺🇸 Houston, Texas, United States