A Multi-Institutional Pilot Study of Allogeneic Hematopoietic Stem Cell Transplantation for Patients With Malignant Neuro-Epithelial and Other Solid Tumors

A Multi-Institutional Pilot Study of Allogeneic Hematopoietic Stem Cell Transplantation for Patients With Malignant Neuro-Epithelial and Other Solid Tumors

A Multi-Institutional Pilot Study of Allogeneic Hematopoietic Stem Cell Transplantation for Patients With Malignant Neuro-Epithelial and Other Solid Tumors

There is currently no standard treatment for patients with neuro-epithelial (brain) or other solid tumors in another part of the body who do not have adequate suitable autologous hematopoietic progenitor cells available and/or whose disease has relapsed after standard treatment. Allogeneic Hematopoietic Progenitor Cell Transplant may be a consideration for treatment of patients with recurrent chemo-responsive malignant (high grade) neuro-epithelial and other solid tumors or those who do not have suitable autologous hematopoietic progenitor cell availability. The procedure in which your own blood stem cells are transplanted to you is called an autologous (from your own) progenitor cell transplant and when cells from a matched donor are transfused is called an allogeneic progenitor cell transplant. The study is being conducted to evaluate the safety and effectiveness of a combination of drugs followed by an allogeneic hematopoietic progenitor cell transplant (HPCT). This treatment regimen is experimental in that although the individual drugs are commonly used to treat your disease, the specific combination used in this protocol followed by the transplant is experimental.

This is a multi-institutional Pilot clinical trial of hematopoietic stem cell transplantation (HSCT) for (i) patients with recurrent chemo-responsive malignant (high-grade) neuro-epithelial and other solid tumors which are recurrent following HSCT or (ii) for said patients without autologous hematopoietic progenitor cell availability. The stem cells will be derived from a 1) matched related donor or 2) matched unrelated donor (MUD). This is a pilot study of a novel HSCT protocol for patients with high-grade and/or recurrent neuro-epithelial and other solid tumors. To determine the feasibility of allogeneic HSCT following thiotepa-based marrow ablative chemotherapy (MAC) for children with high-grade and/or recurrent neuro-epithelial and other solid tumors. The primary end-point for this study is to determine progression-free survival (PFS) at six months post-HSCT. Secondary end-points include: (a) overall survival (OS) at one year (b) transplant related mortality (TRM) at Day +100 (c) engraftment (d) regimen related toxicity: the frequency and severity of acute and chronic graft-versus-host disease (GVHD), sinusoidal obstructive syndrome and infections will be assessed (e) time to immune reconstitution following HSCT. Exploratory Aims include: 1) To assess the feasibility of the Taqman® Low Density Arrays (TLDA) assay as a technology for MRD detection among a subset of patients with high-grade and/or recurrent neuro-epithelial and other solid tumors. Minimal residual disease (MRD) (when applicable) in bone marrow pre- and post-HSCT, will be assessed using TLDA. Currently, for solid malignancies there is no routinely established method to detect minimal residual disease, the first indicator of therapy failure and/or recurrence of disease. 2) In an effort to minimize morbidity related to graft-versus-host disease, alemtuzumab forms an important component of the proposed MAC regimen for recipients of unrelated or related mismatched allogeneic grafts. As an exploratory aim, an alemtuzumab assay will be performed at specified intervals to explore time to drug clearance. This may provide important information regarding lymphodepletion for future trials regarding immunotherapy administered during recovery from HSCT therapy. The main advantages of the proposed approach will: 1) Overcome the challenges in bone morrow/peripheral blood stem cell (PBSC) collection in patients heavily pre-treated and/or bone/bone marrow infiltration with tumor. 2) Eliminate the risk of graft contamination with tumor cells, and 3) Graft-versus-tumor effect (GVT) to eliminate residual disease after conditioning chemotherapy. The use of allografting with the proposed regimen combines the benefits of high dose chemotherapy and an immune approach to disease therapy.

Matched Unrelated Donor HSCT (minimum 9/10 human leukocyte antigen [HLA] match) OR Matched Related Donor HSCT (10/10 HLA match). Conditioning regimen begins 12 days prior to stem cell infusion and includes the following drugs: Keratinocyte Growth Factor Alemtuzumab Thiotepa Etoposide Melphalan Fludarabine Tacrolimus (Cyclosporine A may be substituted for Tacrolimus) Mycophenolate mofetil

Allogeneic hematopoietic stem cell transplant (HSCT) following thiotepa-based marrow ablative chemotherapy (MAC) for children with high-grade and/or recurrent neuro-epithelial and other solid tumors.

Alemtuzumab 12 mg/m2 IV: 2 doses (not given if matched related donor is 10/10 HLA matched sibling donor)

Tacrolimus 0.05 mg/kg/day IV (Cyclosporine may be substituted for Tacrolimus): Start Day -2, begin taper on Day +100, discontinue on Day +180

Cyclosporine A dosed as follows: Age ≤ 6 years: 6 mg/kg/day IV in divided doses (e.g. 2 mg/kg every 8 hours) OR Age > 6 years: 3 mg/kg/day IV in divided doses (1.5 mg/kg every 12 hours): Start Day -2, begin taper on Day +100, discontinue on Day +180

Mycophenolate mofetil 15 mg/kg every 8 hours oral or IV: Start Day 0 (4-6 hours post stem cell infusion) to Day +40, then taper weekly until discontinuation on Day +90

Use of TLDA assay as a technology for MRD detection among a subset of patients with high-grade and/or recurrent neuro-epithelial and other solid tumors.

The Alemtuzumab assay will explore time to drug clearance. This may provide important information regarding lymphodepletion for future trials regarding immunotherapy administered during recovery from HSCT therapy.

Inclusion Criteria: Malignant (high-grade) neuro-epithelial and other solid tumors Patients have to be in at least, a chemo-responsive disease status defined as; any disease regression to chemotherapy when compared to its pre-treatment evaluation Patients with recurrent (or refractory) chemo-responsive disease or without suitable autologous hematopoietic progenitor cell availability Creatinine clearance or glomerular filtration rate (GFR) ≥50 ml/min/1.73m2, and not requiring dialysis Diffusing capacity of lung for carbon monoxide, or DLCO, (corrected for hemoglobin) ≥ 50% predicted. If unable to perform pulmonary function tests, then oxygen (O2) saturation ≥ 92% in room air Bilirubin ≤3x upper limit of normal (ULN) and alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 5x for age (with the exception of isolated hyperbilirubinemia due to Gilbert's syndrome) Exclusion Criteria: Lack of histocompatible suitable related or unrelated donor/ graft source End-organ failure that precludes the ability to tolerate the transplant procedure, including conditioning Renal failure requiring dialysis Congenital heart disease resulting in congestive heart failure Ventilatory failure 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 Female of reproductive potential who is pregnant, planning to become pregnant during the study, or is nursing a child

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